Compositions for the treatment of fibrosis

ABSTRACT

The present disclosure is directed to methods of treating fibrotic conditions by administration of TRβ agonists. The disclosure provides methods wherein the abnormal deposition of extracellular matrix components, such as collagen, keratin, or elastin, is reduced, either through interaction of TRβ agonists with TGF-β-dependent inflammatory pathways, or by other mechanisms, thereby ameliorating fibrotic symptoms.

FIELD

The compositions and methods of the present disclosure relate generallyto the field of treatments for fibrotic disease.

BACKGROUND

Fibrosis is a pathogenic hallmark of a vast number of conditions,implicating a wide variety of tissues, among them the liver (e.g.,non-alcoholic steatohepatitis, glycogen storage disease type IX,cirrhosis), the lung (e.g., chronic interstitial lung disease,pneumoconiosis, silicosis, emphysema, fibrosing lung diseases,idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia,cryptogenic organizing pneumonia), the vasculature (e.g., diffuseinterstitial fibrosis; atherosclerosis), the heart (e.g., cardiacfibrosis; atrial fibrosis; endomyocardial fibrosis), the skin (e.g.,keloid lesions, nephrogenic systemic fibrosis, scleroderma), joints andinterstitial tissues (e.g., arthrofibrosis, Dupuytren's disease), thepancreas (e.g., pancreatitis), the mouth (e.g., fibrous proliferativelesions of the oral cavity), the gut (e.g., fibrosing strictures, forexample, related to Crohn's disease), the brain (glial scarring,leptomeningeal fibrosis associated with bacterial meningitis). Fibrosismay also result from environmental insults or a variety of injuries,such as, for example, exposure to ionizing radiation (such as duringcancer treatments), as a result of cystic rupture in the breast,(causing palpable lesions in mammary tissue), and generally as a resultof overdeposition of collagen following a wound or tissue insult, suchas after injury or surgery.

While some types of fibrosis involve underlying genetic predispositions(e.g., Dupuytren's disease), most types involve prolonged inflammationof the affected tissue (e.g., hepatic fibroses and pneumoconialfibroses). Symptoms may be as minor as pruritis and aesthetic concerns(e.g., in the case of keloid lesions of the skin) or as significant aspulmonary failure and death (e.g., as terminal symptoms of pulmonaryfibroses and cardiac fibroses). While fibrosis is essentiallyirreversible once established, treatments exist to slow the progressionof various fibrotic conditions, or to ameliorate fibrosis or fibroticconditions. Current antifibrotic treatments include anti-inflammatorycompounds such as pirfenidone and fibroblast growth factor receptorantagonist nintedanib. For dermal and subdermal fibroses, examples ofcurrent therapies include surgery, phototherapy and injections ofClostridium histolyticum collagenase. However, due to the irreversiblenature of the various fibroses, as well as the limited efficacy ofcurrent therapies, there remains a need for additional therapeuticapproaches to this class of conditions.

SUMMARY

Disclosed herein are methods of treating fibroses, fibrotic conditionsor fibrotic symptoms in a subject in need thereof comprisingadministering to said subject at least one compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:G is selected from the group consisting of —O—, —S—, —S(O)—, —S(═O)₂—,—Se—, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —CH(C₁-C₄ alkyl)-,—CH(C₁-C₄ alkoxy)-, —C(═CH₂)—, —NH—, and —N(C₁-C₄ alkyl)-;T is selected from the group consisting of —(CR^(a) ₂)_(k)—,—CR^(b)═CR^(b)—(CR^(a) ₂)_(n)—, —(CR^(a) ₂)_(n)—CR^(b)═R^(b)—, —(CR^(a)₂)—CR^(b)═R^(b)—(CR^(a) ₂)—, —O(CR^(b) ₂)(CR^(a) ₂)_(n)—, —S(CR^(b)₂)(CR^(a) ₂)n-, N(R^(c))(CR^(b) ₂)(CR^(a) ₂)_(n)—, N(R^(b))C(O)CR^(a)₂)_(n), —C(O)(CR^(a) ₂)_(m)—, —(CR^(a) ₂)_(m)C(O)—, —(CR^(a)₂)C(O)(CR^(a) ₂)_(n), —(CR^(a) ₂)_(n)C(O)(CR^(a) ₂)—, and —C(O)NH(CR^(b)₂)(CR^(a) ₂)_(p)—;k is an integer from 1-4;m is an integer from 0-3;n is an integer from 0-2;p is an integer from 0-1;each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, optionally substituted —S—C₁-C₄alkyl, —NR^(b)R^(c), optionally substituted —C₂-C₄ alkenyl, andoptionally substituted —C₂-C₄ alkynyl; with the proviso that when oneR^(a) is attached to C through an O, S, or N atom, then the other R^(a)attached to the same C is a hydrogen, or attached via a carbon atom;each R^(b) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl;each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H;R¹, and R² are each independently selected from the group consisting ofhalogen, optionally substituted —C₁-C₄ alkyl, optionally substituted—S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl, optionallysubstituted —C₂-C₄ alkynyl, —CF₃, —OCF₃, optionally substituted-C₁-C₃alkyl, and cyano;R⁶, R⁷, R⁸, and R⁹ are each independently selected from the groupconsisting of are each independently selected from the group consistingof hydrogen, halogen, optionally substituted —CC₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₂, —OCF₃, optionallysubstituted-O—C₁-C₃ alkyl, and cyano; or R⁶ and T are taken togetheralong with the carbons they are attached to form a ring of 5 to 6 atomsincluding 0 to 2 heteroatoms independently selected from —NR^(i)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom; and X is attached tothis ring by a direct bond to a ring carbon, or by —(CR^(a) ₂)— or—C(O)— bonded to a ring carbon or a ring nitrogen;R^(i) is selected from the group consisting of hydrogen, —C(O)C₁-C₄alkyl, —C₁-C₄ alkyl, and —C₁-C₄-aryl;R³ and R⁴ are independently selected from the group consisting ofhydrogen, halogen, —CF₃, —OCF₃, cyano, optionally substituted —C₁-C₁₂alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionally substituted—C₂-C₁₂ alkynyl, —SR^(d), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)OR^(h), —C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g), —N(R^(b))S(═O)₂R^(e),—N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g);each R^(d) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n) aryl, optionally substituted —(CR^(b) ₂)_(n) cycloalkyl,optionally substituted —(CR^(b) ₂)_(n) heterocycloalkyl, and—C(O)NR^(f)R^(g);each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a)₂)_(n) aryl, optionally substituted —(CR^(a) ₂)_(n) cycloalkyl, andoptionally substituted —(CR^(a) ₂)_(n) heterocycloalkyl;R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(b) ₂)_(n) aryl, optionally substituted—(CR^(b) ₂)_(n) cycloalkyl, and optionally substituted —(CR^(b) ₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form an optionallysubstituted heterocyclic ring, which may contain a second heterogroupselected from the group consisting of O, NR^(C), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano, —CF₃, optionallysubstituted phenyl, and —C(O)OR^(h);each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n) aryl, optionally substituted —(CR^(b) ₂)_(n) cycloalkyl, andoptionally substituted —(CR^(b) ₂)_(n) heterocycloalkyl;R⁵ is selected from the group consisting of —OH, optionally substituted—OC₁-C₆ alkyl, OC(O)R^(e), —OC(O)OR^(h), —F, —NHC(O)R^(e),—NHS(═O)R^(e), —NHS(═O)₂R^(e), —NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h));X is P(O)YR¹¹Y′R¹¹;Y and Y′ are each independently selected from the group consisting of—O—, and —NR^(v)—; when Y and Y′ are —O—, R¹¹ attached to —O— isindependently selected from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocycloalkyl,optionally substituted CH₂-heterocycloakyl wherein the cyclic moietycontains a carbonate or thiocarbonate, optionally substituted-alkylaryl, —C(R^(z))₂OC(O)NR^(z) ₂, —NR^(z)—C(O)—R^(y),—C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y), —C(R^(z))₂OC(O)SR^(y),-alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy;when Y and Y′ are —NR^(v)—, then R¹¹ attached to —NR^(v)— isindependently selected from the group consisting of —H,—[C(R^(z))₂]_(q)—COOR^(y), —C(R^(x))₂COOR^(Y),—[C(R^(z))₂]_(q)—C(O)SR^(y), and -cycloalkylene-COOR^(y);when Y is —O— and Y′ is NR^(v), then R¹¹ attached to —O— isindependently selected from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocycloalkyl,optionally substituted CH₂-heterocycloakyl wherein the cyclic moietycontains a carbonate or thiocarbonate, optionally substituted-alkylaryl, —C(R^(z))₂OC(O)NR^(z) ₂, —NR^(z)—C(O)—R^(y),—C(R^(z))₂OC(O)R^(y), —C(R^(z))₂—O—(O)OR^(y), —C(R^(z))₂OC(O)SR^(y),-alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; and R¹¹ attached to —NR^(v)— is independentlyselected from the group consisting of H, —[C(R^(z))₂]_(q)—COOR^(y),C(R^(x))₂COOR^(y), —[C(R^(z))₂]_(q)—(O)SR^(y), and-cycloalkylene-COOR^(y);or when Y and Y′ are independently selected from —O— and NR^(v), thentogether R¹¹ and R¹¹ are -alkyl-S—S-alkyl- to form a cyclic group, ortogether R¹¹ and R¹¹ are the group:

wherein:V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted 1-alkenyl, and optionally substituted1-alkynyl:or together V and Z are connected via an additional 3-5 atoms to form acyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms andthe remaining atoms are carbon, substituted with hydroxy, acyloxy,alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attachedto a carbon atom that is three atoms from both Y groups attached to thephosphorus;or together V and Z are connected via an additional 3-5 atoms to form acyclic group, wherein 0-1 atoms are heteroatoms and the remaining atomsare carbon, that is fused to an aryl group at the beta and gammaposition to the Y attached to the phosphorus;or together V and W are connected via an additional 3 carbon atoms toform an optionally substituted cyclic group containing 6 carbon atomsand substituted with one substituent selected from the group consistingof hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, andaryloxycarbonyloxy, attached to one of said carbon atoms that is threeatoms from a Y attached to the phosphorus;or together Z and W are connected via an additional 3-5 atoms to form acyclic group, wherein 0-1 atoms are heteroatoms and the remaining atomsare carbon, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;or together W and W′ are connected via an additional 2-5 atoms to form acyclic group, wherein 0-2 atoms are heteroatoms and the remaining atomsare carbon, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;Z is selected from the group consisting of —CHR^(z)OH,—CHR^(z)OC(O)R^(y), —CHR^(z)OC(S)R^(y), —CHR^(z)OC(S)OR^(y),—CHR^(z)OC(O)SR^(y), —CHR^(z)OCO₂R^(y), —OR^(z), —SR^(z), —CHR^(z)N₃,—CH₂-aryl, —CH(aryl)OH, —CH(CH═CR^(z) ₂)OH, —CH(C≡CR^(z))OH, —R^(z),—NR^(z) ₂, —OCOR^(y)—, —OCO₂R^(y), —SCOR^(y), —SCO₂R^(y), —NHCOR^(z),—NHCO₂R^(y), —CH₂NH-aryl, —(CH₂)_(q)—OR^(z), and —(CH₂)q-SR^(z);q is an integer 2 or 3;each R^(z) is selected from the group consisting of R^(y) and —H:each R^(y) is selected from the group consisting of alkyl, aryl,heterocycloalkyl, and aralkyl;each R^(x) is independently selected from the group consisting of —H,and alkyl, or together R^(x) and R^(x) form a cyclic alkyl group; andeach R^(v) is selected from the group consisting of —H, lower alkyl,acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl.

According to the methods and compositions described herein, the compoundto be administered may comprise one or more of the compounds having astructure selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

According to the methods and compositions disclosed herein, thecompounds described above may be administered to treat, ameliorate,prevent, or cure one or more fibrotic conditions selected from glycogenstorage disease type III (GSD III), glycogen storage disease type VI(GSD VI), glycogen storage disease type IX (GSD IX), non-alcoholicsteatohepatitis (NASH), cirrhosis, hepatitis, scleroderma, alcoholicfatty liver disease, atherosclerosis, asthma, cardiac fibrosis, organtransplant fibrosis, muscle fibrosis, pancreatic fibrosis, bone-marrowfibrosis, liver fibrosis, cirrhosis of liver and gallbladder, fibrosisof the spleen, pulmonary fibrosis, idiopathic pulmonary fibrosis,diffuse parenchymal lung disease, idiopathic interstitial fibrosis,diffuse interstitial fibrosis, interstitial pneumonitis, desquamativeinterstitial pneumonia, respiratory bronchiolitis, interstitial lungdisease, chronic interstitial lung disease, acute interstitialpneumonitis, hypersensitivity pneumonitis, nonspecific interstitialpneumonia, cryptogenic organizing pneumonia, lymphocytic interstitialpneumonia, pneumoconiosis, silicosis, emphysema, interstitial fibrosis,sarcoidosis, mediastinal fibrosis, cardiac fibrosis, atrial fibrosis,endomyocardial fibrosis, renal fibrosis, chronic kidney disease, Type IIdiabetes, macular degeneration, keloid lesions, hypertrophic scar,nephrogenic systemic fibrosis, injection fibrosis, complications ofsurgery, fibrotic chronic allograft vasculopathy and/or chronicrejection in transplanted organs, fibrosis associated with ischemicreperfusion injury, post-vasectomy pain syndrome, fibrosis associatedwith rheumatoid arthritis, arthrofibrosis, Dupuytren's disease,dermatomyositis-polymyositis, mixed connective tissue disease, fibrousproliferative lesions of the oral cavity, fibrosing intestinalstrictures, Crohn's disease, glial scarring, leptomeningeal fibrosis,meningitis, systemic lupus erythematosus, fibrosis due to radiationexposure, fibrosis due to mammary cystic rupture, myelofibrosis,retroperitoneal fibrosis, progressive massive fibrosis, psoriasis, orsymptoms or sequelae thereof, or other diseases or conditions resultingin the excessive deposition of extracellular matrix components, such ascollagen, which may be affected by interventions within the TRβ pathway,or any combination thereof. The methods and compositions according tothe present disclosure may comprise a primary fibrosis, or a conditionin which said fibrosis, fibrotic condition or fibrotic symptom issecondary to or symptomatic of another condition.

In some embodiments according to the methods and compositions asdisclosed herein, said fibrosis, fibrotic condition or fibrotic symptommay comprise one or more of scleroderma, atherosclerosis, cardiacfibrosis, organ transplant fibrosis, muscle fibrosis, pancreaticfibrosis, bone-marrow fibrosis, liver fibrosis, fibrosis of the spleen,pulmonary fibrosis, idiopathic pulmonary fibrosis, idiopathicinterstitial fibrosis, diffuse interstitial fibrosis, interstitial lungdisease, chronic interstitial lung disease, pneumoconiosis, silicosis,interstitial fibrosis, sarcoidosis, mediastinal fibrosis, cardiacfibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis,macular degeneration, keloid lesions, hypertrophic scar, nephrogenicsystemic fibrosis, injection fibrosis, fibrotic complications ofsurgery, fibrotic chronic allograft vasculopathy, fibrosis associatedwith ischemic reperfusion injury, arthrofibrosis, Dupuytren's disease,fibrous proliferative lesions of the oral cavity, fibrosing intestinalstrictures, glial scarring, leptomeningeal fibrosis, fibrosis due toradiation exposure, fibrosis due to mammary cystic rupture,myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis orany combination thereof.

In some other embodiments, said fibrosis, fibrotic condition or fibroticsymptom may be secondary to one or more of glycogen storage disease typeIII (GSD III), glycogen storage disease type VI (GSD VI), glycogenstorage disease type IX (GSD IX), non-alcoholic steatohepatitis (NASH),cirrhosis, hepatitis, scleroderma, alcoholic fatty liver disease,atherosclerosis, asthma, cirrhosis of the gallbladder, diffuseparenchymal lung disease, interstitial pneumonitis, desquamativeinterstitial pneumonia, respiratory bronchiolitis, interstitial lungdisease, chronic interstitial lung disease, acute interstitialpneumonitis, hypersensitivity pneumonitis, nonspecific interstitialpneumonia, cryptogenic organizing pneumonia, lymphocytic interstitialpneumonia, emphysema, chronic kidney disease, Type II diabetes, maculardegeneration, chronic rejection in transplanted organs, post-vasectomypain syndrome, rheumatoid arthritis, dermatomyositis-polymyositis, mixedconnective tissue disease, Crohn's disease, meningitis, systemic lupuserythematosus, or symptoms or sequelae thereof, or other diseases orconditions resulting in the excessive deposition of extracellular matrixcomponents, such as collagen, which may be affected by interventionswithin the TRβ pathway, or any combination thereof.

In some other embodiments, said fibrosis, fibrotic condition or fibroticsymptom may comprise a symptom or sequela of GSD III, GSD IX, NonAlcoholic Steatohepatitis, cirrhosis of the liver or pancreas,Dupuytren's disease, scleroderma, idiopathic pulmonary fibrosis, oralcoholic fatty liver disease, or any combination thereof.

The methods and compositions of the present disclosure may furthercomprise a method of treating a fibrosis, a fibrotic condition or afibrotic symptom in a subject, comprising administering one or more of

to a subject in need thereof.

The methods and compositions according to the present disclosure furtherprovide for the administration of one or more of the compounds listedabove to a subject, wherein said subject has one or more conditionsselected from glycogen storage disease type III (GSD III), glycogenstorage disease type VI (GSD VI), glycogen storage disease type IX (GSDIX), hepatitis, scleroderma, atherosclerosis, asthma, cardiac fibrosis,organ transplant fibrosis, muscle fibrosis, pancreatic fibrosis,bone-marrow fibrosis, liver fibrosis, cirrhosis of the gallbladder,fibrosis of the spleen, pulmonary fibrosis, idiopathic pulmonaryfibrosis, diffuse parenchymal lung disease, idiopathic interstitialfibrosis, diffuse interstitial fibrosis, interstitial pneumonitis,desquamative interstitial pneumonia, respiratory bronchiolitis,interstitial lung disease, chronic interstitial lung disease, acuteinterstitial pneumonitis, hypersensitivity pneumonitis, nonspecificinterstitial pneumonia, cryptogenic organizing pneumonia, lymphocyticinterstitial pneumonia, pneumoconiosis, silicosis, emphysema,interstitial fibrosis, sarcoidosis, mediastinal fibrosis, cardiacfibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis,chronic kidney disease, Type II diabetes, macular degeneration, keloidlesions, hypertrophic scar, nephrogenic systemic fibrosis, injectionfibrosis, complications of surgery, fibrotic chronic allograftvasculopathy and/or chronic rejection in transplanted organs, fibrosisassociated with ischemic reperfusion injury, post-vasectomy painsyndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis,Dupuytren's disease, dermatomyositis-polymyositis, mixed connectivetissue disease, fibrous proliferative lesions of the oral cavity,fibrosing intestinal strictures, Crohn's disease, glial scarring,leptomeningeal fibrosis, meningitis, systemic lupus erythematosus,fibrosis due to radiation exposure, fibrosis due to mammary cysticrupture, myelofibrosis, retroperitoneal fibrosis, progressive massivefibrosis, or symptoms or sequelae thereof, or other diseases orconditions resulting in the excessive deposition of extracellular matrixcomponents, such as collagen, which may be affected by interventionswithin the TRβ pathway, or any combination thereof. The methods andcompositions of the present disclosure contemplate said administrationwherein the condition is a primary fibrosis, a secondary fibrosis, or afibrotic symptom of a condition.

According to the methods and compositions of the present disclosure, aprimary fibrosis may comprise one or more of scleroderma,atherosclerosis, cardiac fibrosis, organ transplant fibrosis, musclefibrosis, pancreatic fibrosis, bone-marrow fibrosis, liver fibrosis,fibrosis of the spleen, pulmonary fibrosis, idiopathic pulmonaryfibrosis, idiopathic interstitial fibrosis, diffuse interstitialfibrosis, interstitial lung disease, chronic interstitial lung disease,pneumoconiosis, silicosis, interstitial fibrosis, sarcoidosis,mediastinal fibrosis, cardiac fibrosis, atrial fibrosis, endomyocardialfibrosis, renal fibrosis, macular degeneration, keloid lesions,hypertrophic scar, nephrogenic systemic fibrosis, injection fibrosis,fibrotic complications of surgery, fibrotic chronic allograftvasculopathy, fibrosis associated with ischemic reperfusion injury,arthrofibrosis, Dupuytren's disease, fibrous proliferative lesions ofthe oral cavity, fibrosing intestinal strictures, glial scarring,leptomeningeal fibrosis, fibrosis due to radiation exposure, fibrosisdue to mammary cystic rupture, myelofibrosis, retroperitoneal fibrosis,progressive massive fibrosis or any combination thereof.

According to the methods and compositions of the present disclosure, asecondary fibrosis may comprise a fibrosis associated with one or moreof glycogen storage disease type III (GSD III), glycogen storage diseasetype VI (GSD VI), glycogen storage disease type IX (GSD IX), hepatitis,scleroderma, atherosclerosis, asthma, cirrhosis of the gallbladder,diffuse parenchymal lung disease, interstitial pneumonitis, desquamativeinterstitial pneumonia, respiratory bronchiolitis, interstitial lungdisease, chronic interstitial lung disease, acute interstitialpneumonitis, hypersensitivity pneumonitis, nonspecific interstitialpneumonia, cryptogenic organizing pneumonia, lymphocytic interstitialpneumonia, emphysema, chronic kidney disease, Type II diabetes, maculardegeneration, chronic rejection in transplanted organs, post-vasectomypain syndrome, rheumatoid arthritis, dermatomyositis-polymyositis, mixedconnective tissue disease, Crohn's disease, meningitis, systemic lupuserythematosus, or symptoms or sequelae thereof, or other diseases orconditions resulting in the excessive deposition of extracellular matrixcomponents, such as collagen, which may be affected by interventionswithin the TRβ pathway, or any combination thereof.

According to the methods and compositions of the present disclosure, aprimary fibrosis may comprise a symptom or sequela of GSD III, GSD IX,cirrhosis of the pancreas, Dupuytren's disease, scleroderma, idiopathicpulmonary fibrosis, or alcoholic fatty liver disease, or any combinationthereof.

According to the methods and compositions of the present disclosure, thecompositions to be administered may further comprise one or morepharmaceutically acceptable excipients, and may be formulated for oral,intravenous, intraarterial, intestinal, rectal, vaginal, nasal,pulmonary, topical, intradermal, transdermal, transbuccal, translingual,sublingual, or opthalmic administration, or any combination thereof.

According to the methods and compositions of the present disclosure, asubject to which the compositions listed above are to be administeredmay show abnormal or excessive deposition of collagen type 1, 1a, orIII. In some embodiments according to the methods and compositions ofthe present disclosure, administration of said composition results inthe prevention, amelioration, or cure of said fibrosis, fibroticcondition, or fibrotic symptom, and may further result in the reductionin the amount of extracellular matrix proteins present in one or moretissues of said subject. In some embodiments, said reduction in theamount of extracellular matrix proteins present in one or more tissuesof said subject may comprise a reduction in the amount of collagenpresent in one or more tissues of said subject, and may further comprisea reduction in the amount of Type I, Type Ia, or Type I collagen presentin one or more tissues of said subject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows total liver hydroxyproline content in mice following 8weeks of treatment with vehicle, low dose Compound 2 (see Example 1),high dose Compound 2 (see Example 1), Compound 1, or elafibranor(control). Compound 2-treated animals show lower total liverhydroxyproline levels than control-treated or mock-treated animals.

FIG. 2 shows representative images of liver stained with Picro-SiriusRed (to visualize collagen I and III deposition, red stain) at the endof the treatment period following 8 weeks of treatment with vehicle, lowdose Compound 2 (see Example 1), high dose Compound 2 (see Example 1),Compound 1, or elafibranor (control) (magnification 10×, scale bar=200μm).

FIG. 3 shows representative images of liver stained with anti-type Icollagen (colla1) (Southern Biotech, Cat. 131001) at the end of thetreatment period following 8 weeks of treatment with vehicle, low doseCompound 2 (see Example 1), high dose Compound 2 (see Example 1),Compound 1, or elafibranor (control) (magnification 20×, scale bar=100m).

FIG. 4 shows total Liver ColA1 content post-biopsy following 8 weeks oftreatment with vehicle, low dose Compound 2 (see Example 1), high doseCompound 2 (see Example 1), Compound 1, or elafibranor (control).Compound 2-treated animals show lower total liver ColA1 content thancontrol-treated or mock-treated animals.

FIG. 5 shows liver Picro-Sirius Red (PSR) staining, post-biopsy, asdetermined by histological quantitative assessment following 8 weeks oftreatment with vehicle, low dose Compound 2 (see Example 1), high doseCompound 2 (see Example 1), Compound 1, or elafibranor (control). Total(mg/liver) liver collagen 1 and 3 were determined by morphometryfollowing Picro-Sirius Red staining. Liver sections fromCompound-1-treated animals showed lower PSR staining than those frommock-treated animals; liver sections from Compound 2-treated animalsshowed lower PSR staining than control-treated or mock-treated animals.Data expressed as mean±SEM (n=11-12).

FIG. 6 shows the percent reduction in total liver triglycerides,cholesterol, and lipids as well as the percent reduction in NAS forCompound 2-treated animals vs. vehicle-treated controls following 8weeks of dosing with Compound 2 in a diet-induced mouse model of NASH(See Example 6).

FIG. 7 shows the percent reduction in liver fibrosis for Compound2-treated animals vs. vehicle-treated controls following 8 weeks ofdosing with Compound 2 in a diet-induced mouse model of NASH (SeeExample 6). Liver fibrosis is assessed in terms of fibrosis score, thelevel of Type I collagen present, and the level of hydroxyprolinepresent in post-treatment liver samples.

FIG. 8 shows the percent reduction in pro-fibrogenic gene expression forCompound 2-treated animals vs. vehicle-treated controls following 8weeks of dosing with Compound 2 in a diet-induced mouse model of NASH(See Example 6). Pro-fibrogenic gene expression is assessed in terms ofthe levels of expression of Cola1, Col3α1, αSMA, and Galectin 1 inpost-treatment liver samples.

DETAILED DESCRIPTION

The present disclosure provides compounds and methods for treatingfibrosis, fibrotic conditions, or fibrotic symptoms by administeringthyroid hormone receptor-β (TRβ) agonists. In some embodiments, suchfibrosis, fibrotic conditions, or conditions giving rise to fibroticsymptoms may include glycogen storage disease type III (GSD III),glycogen storage disease type VI (GSD VI), glycogen storage disease typeIX (GSD IX), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatitis,scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma,cardiac fibrosis, organ transplant fibrosis, muscle fibrosis, pancreaticfibrosis, bone-marrow fibrosis, liver fibrosis, cirrhosis of liver andgallbladder, fibrosis of the spleen, scleroderma, pulmonary fibrosis,idiopathic pulmonary fibrosis, diffuse parenchymal lung disease,idiopathic interstitial fibrosis, diffuse interstitial fibrosis,interstitial pneumonitis, desquamative interstitial pneumonia,respiratory bronchiolitis, interstitial lung disease, chronicinterstitial lung disease, acute interstitial pneumonitis,hypersensitivity pneumonitis, nonspecific interstitial pneumonia,cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia,pneumoconiosis, silicosis, emphysema, interstitial fibrosis,sarcoidosis, mediastinal fibrosis, cardiac fibrosis, atrial fibrosis,endomyocardial fibrosis, renal fibrosis, chronic kidney disease, Type IIdiabetes, macular degeneration, keloid lesions, hypertrophic scar,nephrogenic systemic fibrosis, injection fibrosis, complications ofsurgery, fibrotic chronic allograft vasculopathy and/or chronicrejection in transplanted organs, fibrosis associated with ischemicreperfusion injury, post-vasectomy pain syndrome, fibrosis associatedwith rheumatoid arthritis, arthrofibrosis, Dupuytren's disease,dermatomyositis-polymyositis, mixed connective tissue disease, fibrousproliferative lesions of the oral cavity, fibrosing intestinalstrictures, Crohn's disease, glial scarring, leptomeningeal fibrosis,meningitis, systemic lupus erythematosus, fibrosis due to radiationexposure, fibrosis due to mammary cystic rupture, myelofibrosis,retroperitoneal fibrosis, progressive massive fibrosis, or symptoms orsequelae thereof, or other diseases or conditions resulting in theexcessive deposition of extracellular matrix components, such ascollagen, which may be affected by interventions within the TRβ pathway.Such conditions may be associated with inflammation and/or injury, andfurther may involve responses mediated by TGF-β-dependent pathways whichcan be modulated by thyroid hormones (see, e.g., Alfonso-Merino et al.,Proc. Nat. Acad. Sci. 113(24):E3451-60 (2016), which is incorporatedherein for its disclosure of the ability of thyroid hormones to modulateTGF-β signaling and related fibrosis in mice). Because TGF-β-dependentpathways are implicated in fibroblast differentiation and thestimulation of collagen production, and thyroid hormones such as T3 andT4 may impinge on these pathways via the TRβ receptor, the presentdisclosure provides compositions and methods for the prevention,amelioration, or reduction in collagen deposition in one or more tissuesof a subject by administering TRβ agonist compounds.

Definitions

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes humans and non-human mammals such as dogs, cats,horses, donkeys, mules, cows, domestic buffaloes, camels, llamas,alpacas, bison, yaks, goats, sheep, pigs, elk, deer, domestic antelopes,and non-human primates as well as many other species.

“Subject” as used herein, means a human or a non-human mammal includingbut not limited to a dog, cat, horse, donkey, mule, cow, domesticbuffalo, camel, llama, alpaca, bison, yak, goat, sheep, pig, elk, deer,domestic antelope, or a non-human primate selected for treatment ortherapy.

“Subject suspected of having” means a subject exhibiting one or moreclinical indicators of a disease or condition. In certain embodiments,the disease or condition is one or more fibroses, fibrotic conditions,or fibrotic symptoms. In certain embodiments, the disease or conditionis scleroderma. In certain embodiments, the disease or condition isnon-alcoholic steatohepatitis. In certain embodiments, the disease orcondition is cirrhosis. In certain embodiments, the disease or conditionis non-alcoholic fatty liver disease. In certain embodiments, thedisease or condition is idiopathic pulmonary fibrosis. In certainembodiments, the disease or condition is atherosclerosis. In certainembodiments, the disease or condition is hepatitis, alcoholic fattyliver disease, asthma, cardiac fibrosis, organ transplant fibrosis,muscle fibrosis, pancreatic fibrosis, bone-marrow fibrosis, liverfibrosis, cirrhosis of liver and gallbladder, fibrosis of the spleen,scleroderma, pulmonary fibrosis, diffuse parenchymal lung disease,idiopathic interstitial fibrosis, diffuse interstitial fibrosis;interstitial pneumonitis, desquamative interstitial pneumonia,respiratory bronchiolitis, interstitial lung disease, chronicinterstitial lung disease, acute interstitial pneumonitis,hypersensitivity pneumonitis, nonspecific interstitial pneumonia,cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia,pneumoconiosis, silicosis, emphysema, interstitial fibrosis,sarcoidosis, mediastinal fibrosis, cardiac fibrosis, atrial fibrosis,endomyocardial fibrosis, renal fibrosis, chronic kidney disease, Type IIdiabetes, macular degeneration, keloid lesions, hypertrophic scar,nephrogenic systemic fibrosis, injection fibrosis, complications ofsurgery, fibrotic chronic allograft vasculopathy and/or chronicrejection in transplanted organs, fibrosis associated with ischemicreperfusion injury, post-vasectomy pain syndrome, fibrosis associatedwith rheumatoid arthritis, arthrofibrosis, Dupuytren's disease,dermatomyositis-polymyositis, mixed connective tissue disease, fibrousproliferative lesions of the oral cavity, fibrosing intestinalstrictures, Crohn's disease, glial scarring, leptomeningeal fibrosis,meningitis, systemic lupus erythematosus, fibrosis due to radiationexposure, fibrosis due to mammary cystic rupture, myelofibrosis,retroperitoneal fibrosis, progressive massive fibrosis, or symptoms orsequelae thereof, or other diseases or conditions resulting in theexcessive deposition of extracellular matrix components.

As used herein, “fibrosis” refers to the abnormal deposition ofextracellular matrix proteins. Such proteins include but are not limitedto collagen, elastin, fibronectin, laminin, keratin, keratin, keratinsulfate, fibrin, perlecan, agrin, or agrecan. As used herein, “collagen”refers to any one of the subtypes of collagen, including but not limitedto Type I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV,XVI, XVII, or XVIII. Exemplary collagen types and subtypes especiallyinclude Type I, Type Ia, Type II, Type III, Type IV, and Type V. As usedherein, fibrosis may occur by itself or as a symptom or sequela ofanother condition. As used herein, fibrosis may result from a geneticcondition, a genetic predisposition, an environmental insult, an injury,healing of an injury, an autoimmune condition, or a chronicinflammation, a chronic inflammatory condition, or another conditionleading to abnormal or excessive deposition of extracellular matrixcomponents. Fibrosis as referred to herein may be assessed by assayingfor, or determining the presence or level of, one or more biomarkers.Biomarkers for the presence of fibrosis include, but are not limited to,expression of the Cola1, Col3a1, αSMA, and/or Galectin1 genes or anycombination or product thereof. Diagnosis or assessment of fibrosis mayfurther be made by determination of the presence or level of type Icollagen and/or hydroxyproline or any combination or product thereof.Diagnosis or assessment of fibrosis may also be made by histological,histochemical, or immunohistochemical analysis of one or more samplesfrom a subject.

“Glycogen storage disease” means any one or more of a group of disordersmarked by dysfunction in the synthesis, transport, or utilization ofglycogen, generally due to the loss of a necessary enzyme activity.Glycogen storage diseases are generally classified by type according totheir symptoms and etiologies. Known types include GSD type 0(aglycogenesis, glycogen synthase deficiency); GSD type 1 (von Gierkedisease, glucose-6-phosphatase translocase/transporter deficiency, GSDI); GSD type 2 (Pompe disease, alpha-1-4-glucosidase deficiency, GSDII); GSD type 3 (Cori disease, Forbes disease, limit dextrinosis,debranching enzyme disease; amylo-1-6-glucosidase deficiency due to lossof glucosidase, and/or transferase activity, GSD III); GSD type 4(Andersen disease, glycogen phosphorylase deficiency, brancherdeficiency, amylopectinosis, glycogen branching enzyme deficiency;amylo-1,4 to 1,6 transglucosidase deficiency, GSD IV); GSD type 5(McArdle disease; glycogen phosphorylase (muscle type) deficiency, GSDV); GSD type 6 (Hers disease; glycogen phosphorylase E (liver type)deficiency, GSD VI); GSD type 7 (Tarui disease; phosphofructokinasedeficiency, GSD VII); GSD type 8, 9 (GSD with phosphorylase activationsystem defects; phosphorylase kinase (liver or muscle isoforms)deficiency, GSD VIII and GSD IX); GSD type 10 (cyclic AMP-dependentkinase deficiency, GSD X); GSD type 11 (Fanconi-Bickel syndrome; glucosetransporter type 2 (GLUT2) deficiency, GSD XI); and GSD type 12(aldolase A deficiency, GSD XII). Subtypes of glycogen storage diseasesare also known, in particular GSD 1a, which results from mutations inthe gene for glucose-6-phosphatase (G6PC) and leads to, among othersymptoms, the excess accumulation of glycogen and lipids in livertissue, hepatomegaly, hepatic adenomas, and hepatocellular carcinoma.Symptoms of glycogen storage diseases may include elevated or reducedblood sugar, insulin insensitivity, myopathies, as well as hepaticsymptoms such as steatosis, hyperlipidemia, hypercholesterolemia,cardiomegaly, hepatomegaly, fibrosis, cirrhosis, hepatocellular adenoma,and hepatocellular carcinoma. Symptoms may also include insulininsensitivity, elevated or reduced blood glucose, renal dysfunction,and/or fibrosis.

“Subject in need thereof” means a subject identified as in need of atherapy or treatment.

A therapeutic effect relieves, to some extent, one or more of thesymptoms of a disease or disorder, and includes curing the disease ordisorder. “Curing” means that the symptoms of active disease areeliminated. However, certain long-term or permanent effects of thedisease may exist even after a cure is obtained (such as extensivetissue damage).

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a pharmaceutical composition for prophylactic and/ortherapeutic purposes. The term “prophylactic treatment” refers totreating a patient who does not yet have the relevant disease ordisorder, but who is susceptible to, or otherwise at risk of, aparticular disease or disorder, whereby the treatment reduces thelikelihood that the patient will develop the disease or disorder. Theterm “therapeutic treatment” refers to administering treatment to apatient already having a disease or disorder.

“Preventing” or “prevention” refers to delaying or forestalling theonset, development or progression of a condition or disease for a periodof time, including weeks, months, or years.

“Amelioration” means a lessening of severity of at least one indicatorof a condition or disease. In certain embodiments, amelioration includesa delay or slowing in the progression of one or more indicators of acondition or disease. The severity of indicators may be determined bysubjective or objective measures which are known to those skilled in theart.

“Modulation” means a perturbation of function or activity. In certainembodiments, modulation means an increase in gene expression. In certainembodiments, modulation means a decrease in gene expression. In certainembodiments, modulation means an increase or decrease in total serumlevels of a specific protein. In certain embodiments, modulation meansan increase or decrease in free serum levels of a specific protein. Incertain embodiments, modulation means an increase or decrease in totalserum levels of a specific non-protein factor. In certain embodiments,modulation means an increase or decrease in free serum levels of aspecific non-protein factor. In certain embodiments, modulation means anincrease or decrease in total bioavailability of a specific protein. Incertain embodiments, modulation means an increase or decrease in totalbioavailability of a specific non-protein factor.

“Administering” means providing a pharmaceutical agent or composition toa subject, and includes, but is not limited to, administering by amedical professional and self-administering.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butnot limited to, orally, subcutaneously, intravenously, intranasally,topically, transdermally, intraperitoneally, intramuscularly,intrapulmonarilly, vaginally, rectally, or intraocularly. Oral andparenteral administrations are customary in treating the indicationsthat are the subject of the preferred embodiments.

“Parenteral administration,” means administration through injection orinfusion. Parenteral administration includes, but is not limited to,subcutaneous administration, intravenous administration, intramuscularadministration, intraarterial administration, and intracranialadministration.

“Subcutaneous administration” means administration just below the skin.

“Intravenous administration” means administration into a vein.

“Intraarterial administration” means administration into an artery.

The term “agent” includes any substance, molecule, element, compound,entity, or a combination thereof. It includes, but is not limited to,e.g., protein, polypeptide, peptide or mimetic, small organic molecule,polysaccharide, polynucleotide, and the like. It can be a naturalproduct, a synthetic compound, or a chemical compound, or a combinationof two or more substances.

“Pharmaceutical agent” means a substance that provides a therapeuticeffect when administered to a subject.

“Pharmaceutical composition” means a mixture of substances suitable foradministering to an individual that includes a pharmaceutical agent. Forexample, a pharmaceutical composition may comprise a modifiedoligonucleotide and a sterile aqueous solution.

“Active pharmaceutical ingredient” means the substance in apharmaceutical composition that provides a desired effect.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds with whichthey are associated and, which are not biologically or otherwiseundesirable. In many cases, the compounds herein are capable of formingacid and/or base salts by virtue of the presence of phenol and/orphosphonate groups or groups similar thereto. One of ordinary skill inthe art will be aware that the protonation state of any or all of thesecompounds may vary with pH and ionic character of the surroundingsolution, and thus the present disclosure contemplates multiple chargestates of each compound. Pharmaceutically acceptable acid addition saltscan be formed with inorganic acids and organic acids. Inorganic acidsfrom which salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like; particularly preferred are the ammonium,potassium, sodium, calcium and magnesium salts. Organic bases from whichsalts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike, specifically such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. Many such salts areknown in the art, as described in WO 87/05297, Johnston et al.,published Sep. 11, 1987 (incorporated by reference herein in itsentirety).

“Solvate” refers to the compound formed by the interaction of a solventand an EPI, a metabolite, or salt thereof. Suitable solvates arepharmaceutically acceptable solvates including hydrates.

The term “atherosclerosis” refers to a condition characterized byirregularly distributed lipid deposits in the intima of large andmedium-sized arteries wherein such deposits provoke fibrosis andcalcification. Atherosclerosis raises the risk of angina, stroke, heartattack, or other cardiac or cardiovascular conditions.

Compounds

In some embodiments, the TRβ agonists for use as described hereininclude compounds according to Formula I:

wherein:

G is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)₂—,—Se—, —CH₂—, —CF₂—, —CHF—, —C(O)—, —CH(OH)—, —CH(C₁-C₄ alkyl)-,—CH(C₁-C₄ alkoxy)-, —C(═CH₂)—, —NH—, and —N(C₁-C₄ alkyl)-;

T is selected from the group consisting of —(CR^(a) ₂)_(k)—,—CR^(b)═R^(b)—(CR^(a) ₂)_(n), —(CR^(a) ₂)—CR^(b)═CR^(b)—, —(CR^(a)₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, —O(CR^(b) ₂)(CR^(a) ₂)_(n)—, —S(CR^(b)₂)(CR^(a) ₂)n-, N(R^(c))(CR^(b) ₂)(CR^(a) ₂)_(n)—, N(R^(b))C(O)(CR^(a)₂)_(n), —C(O)(CR^(a) ₂)_(m)—, —(CR^(a) ₂)_(m)C(O)—, —(CR^(a)₂)C(O)(CR^(a) ₂)_(n), —(CR^(a) ₂)_(n)C(O)(CR^(a) ₂)—, and —C(O)NH(CR^(b)₂)(CR^(a) ₂)_(p)—;

k is an integer from 1-4;

m is an integer from 0-3;

n is an integer from 0-2;

p is an integer from 0-1;

each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, optionally substituted —S—C₁-C₄alkyl, —NR^(b)R^(c), optionally substituted —C₂-C₄ alkenyl, andoptionally substituted —C₂-C₄ alkynyl; with the proviso that when oneR^(a) is attached to C through an O, S, or N atom, then the other R^(a)attached to the same C is a hydrogen, or attached via a carbon atom;

each R^(b) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl;

each R^(c) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl, optionally substituted—C(O)—C₁-C₄ alkyl, and —C(O)H;

R¹, and R² are each independently selected from the group consisting ofhalogen, optionally substituted —C₁-C₄ alkyl, optionally substituted—S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl, optionallysubstituted —C₂-C₄ alkynyl, —CF₃, —OCF₃, optionally substituted-O—C₁-C₃alkyl, and cyano;

R⁶, R⁷, R⁸, and R⁹ are each independently selected from the groupconsisting of are each independently selected from the group consistingof hydrogen, halogen, optionally substituted —CC₁-C₄ alkyl, optionallysubstituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄ alkenyl,optionally substituted —C₂-C₄ alkynyl, —CF₃, —OCF₃, optionallysubstituted-O—C₁-C₃ alkyl, and cyano; or R⁶ and T are taken togetheralong with the carbons they are attached to form a ring of 5 to 6 atomsincluding 0 to 2 heteroatoms independently selected from —NR^(i)—, —O—,and —S—, with the proviso that when there are 2 heteroatoms in the ringand both heteroatoms are different than nitrogen then both heteroatomshave to be separated by at least one carbon atom; and X is attached tothis ring by a direct bond to a ring carbon, or by —(CR^(a) ₂)— or—C(O)— bonded to a ring carbon or a ring nitrogen;

R^(i) is selected from the group consisting of hydrogen, —C(O)C₁-C₄alkyl, —C₁-C₄ alkyl, and —C₁-C₄-aryl;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, halogen, —CF₃, —OCF₃, cyano, optionally substituted —C₁-C₁₂alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionally substituted—C₂-C₁₂ alkynyl, —SR^(d), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g),—C(O)OR^(h), —C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g), —N(R^(b))S(═O)₂R^(e),—N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g);

each R^(d) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n) aryl, optionally substituted —(CR^(b) ₂)_(n) cycloalkyl,optionally substituted —(CR^(b) ₂)_(n) heterocycloalkyl, and—C(O)NR^(f)R^(g);

each R^(e) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(a)₂)_(n) aryl, optionally substituted —(CR^(a) ₂)_(n) cycloalkyl, andoptionally substituted —(CR^(a) ₂)_(n) heterocycloalkyl;

R^(f) and R^(g) are each independently selected from the groupconsisting of hydrogen, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,optionally substituted —(CR^(b) ₂)_(n) aryl, optionally substituted—(CR^(b) ₂)_(n) cycloalkyl, and optionally substituted —(CR^(b) ₂)_(n)heterocycloalkyl, or R^(f) and R^(g) may together form an optionallysubstituted heterocyclic ring, which may contain a second heterogroupselected from the group consisting of O, NR^(C), and S, wherein saidoptionally substituted heterocyclic ring may be substituted with 0-4substituents selected from the group consisting of optionallysubstituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano, —CF₃, optionallysubstituted phenyl, and —C(O)OR^(h);

each R^(h) is selected from the group consisting of optionallysubstituted —C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl,optionally substituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b)₂)_(n) aryl, optionally substituted —(CR^(b) ₂)_(n) cycloalkyl, andoptionally substituted —(CR^(b) ₂)_(n) heterocycloalkyl;

R⁵ is selected from the group consisting of —OH, optionally substituted—OC₁-C₆ alkyl, OC(O)R^(e), —OC(O)OR^(h), —F, —NHC(O)R^(e),—NHS(═O)R^(e), —NHS(═O)₂R^(e), —NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h));

X is P(O)YR¹¹Y′R¹¹;

Y and Y′ are each independently selected from the group consisting of—O—, and —NR^(v)—; when Y and Y′ are —O—, R¹¹ attached to —O— isindependently selected from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocycloalkyl,optionally substituted CH₂-heterocycloakyl wherein the cyclic moietycontains a carbonate or thiocarbonate, optionally substituted-alkylaryl, —C(R^(z))₂OC(O)NR^(z) ₂, —NR^(z)—C(O)—R^(y),—C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y), —C(R^(z))₂OC(O)SR^(y),-alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy;

when Y and Y′ are —NR^(v)—, then R¹¹ attached to —NR^(v)— isindependently selected from the group consisting of —H,—[C(R^(z))₂]_(q)—COOR^(y), —C(R^(x))₂COOR^(Y),—[C(R^(z))₂]_(q)—C(O)SR^(y), and -cycloalkylene-COOR^(y);

when Y is —O— and Y′ is NR^(v), then R¹¹ attached to —O— isindependently selected from the group consisting of —H, alkyl,optionally substituted aryl, optionally substituted heterocycloalkyl,optionally substituted CH₂-heterocycloakyl wherein the cyclic moietycontains a carbonate or thiocarbonate, optionally substituted-alkylaryl, —C(R^(z))₂OC(O)NR^(z) ₂, —NR^(z)—C(O)—R^(y),—C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y), —C(R^(z))₂OC(O)SR^(y),-alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; and R¹¹ attached to —NR^(v)— is independentlyselected from the group consisting of H, —[C(R^(z))₂]_(q)—COOR^(y),—C(R^(x))₂COOR^(y), —[C(R^(z))₂]_(q)—C(O)SR^(y), and-cycloalkylene-COOR^(y);

or when Y and Y′ are independently selected from —O— and NR^(v), thentogether R¹¹ and R¹¹ are -alkyl-S—S-alkyl- to form a cyclic group, ortogether R¹¹ and R¹¹ are the group:

wherein:

V, W, and W′ are independently selected from the group consisting ofhydrogen, optionally substituted alkyl, optionally substituted aralkyl,heterocycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, optionally substituted 1-alkenyl, and optionally substituted1-alkynyl;

or together V and Z are connected via an additional 3-5 atoms to form acyclic group containing 5-7 atoms, wherein 0-1 atoms are heteroatoms andthe remaining atoms are carbon, substituted with hydroxy, acyloxy,alkylthiocarbonyloxy, alkoxycarbonyloxy, or aryloxycarbonyloxy attachedto a carbon atom that is three atoms from both Y groups attached to thephosphorus;

or together V and Z are connected via an additional 3-5 atoms to form acyclic group, wherein 0-1 atoms are heteroatoms and the remaining atomsare carbon, that is fused to an aryl group at the beta and gammaposition to the Y attached to the phosphorus;

or together V and W are connected via an additional 3 carbon atoms toform an optionally substituted cyclic group containing 6 carbon atomsand substituted with one substituent selected from the group consistingof hydroxy, acyloxy, alkoxycarbonyloxy, alkylthiocarbonyloxy, andaryloxycarbonyloxy, attached to one of said carbon atoms that is threeatoms from a Y attached to the phosphorus;

or together Z and W are connected via an additional 3-5 atoms to form acyclic group, wherein 0-1 atoms are heteroatoms and the remaining atomsare carbon, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

or together W and W′ are connected via an additional 2-5 atoms to form acyclic group, wherein 0-2 atoms are heteroatoms and the remaining atomsare carbon, and V must be aryl, substituted aryl, heteroaryl, orsubstituted heteroaryl;

Z is selected from the group consisting of —CHR^(z)OH,—CHR^(z)OC(O)R^(y), —CHR^(z)OC(S)R^(y), —CHR^(z)OC(S)OR^(y),—CHR^(z)OC(O)SR^(y), —CHR^(z)OCO₂R^(y), —OR^(z), —SR^(z), —CHR^(z)N₃,—CH₂-aryl, —CH(aryl)OH, —CH(CH═CR^(z) ₂)OH, —CH(C≡CR^(z))OH, —R^(z),—NR^(z) ₂, —OCOR^(y), —OCO₂R^(y), —SCOR^(y), —SCO₂R^(y), —NHCOR^(z),—NHCO₂R^(y), —CH₂NH-aryl, —(CH₂)_(q)—OR^(z), and —(CH₂)q-SR^(z);

q is an integer 2 or 3;

each R^(z) is selected from the group consisting of R^(y) and —H:

each R^(y) is selected from the group consisting of alkyl, aryl,heterocycloalkyl, and aralkyl;

each R^(x) is independently selected from the group consisting of —H,and alkyl, or together R^(x) and R^(x) form a cyclic alkyl group;

each R^(v) is selected from the group consisting of —H, lower alkyl,acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;

and pharmaceutically acceptable salts thereof.

In some embodiments, the compound of Formula I has the followingprovisos:

a) when G is —O—, T is —CH₂—, R¹ and R² are each bromo, R³ isiso-propyl, R⁴ is hydrogen, and R⁵ is —OH, then X is not P(O)(OH)₂ orP(O)(OCH₂CH₃)₂;

b) V, Z, W, W′ are not all —H; and

c) when Z is —R^(z), then at least one of V, W, and W′ is not —H, alkyl,aralkyl, or heterocycloalkyl;

d) when G is —O—, T is —(CH₂)₁₋₄—, R¹ and R² are independently halogen,alkyl, and cycloalkyl, R³ is alkyl, R⁴ is hydrogen, and R⁵ is —OH, thenX is not —P(O)(OH)₂ or —P(OX)(O-lower alkyl)₂; and

e) when G is —O—, R⁵ is —NHC(O)R^(e), —NHS(═O)₁₋₂R^(e),—NHC(S)NH(R^(b)), or —NHC(O)NH(R^(h)), T is —(CH₂)^(m)—, —CH═CH—,—O(CH₂)₁₋₂—, or —NH(CH₂)₁₋₂—, then X is not —P(O)(OH)₂ or —P(O)(OH)NH₂.

In some embodiments, the compound is selected from one or more of thefollowing:

or pharmaceutically acceptable salts thereof.

In other embodiments, the compound is selected from:

Structure Compound Number

17

7

1a

12-1

2a

3a

4a

5

6

8

9

11

10

cis-13-1

trans-13-1

cis-13-6

cis-13-2

trans-13-2

cis-13-3

trans-13-3

trans-13-6

12-3

trans-13-5

cis-13-5

trans-13-7

trans-13-4

cis-13-4

12-2

cis-13-7

14

15-1

15-2

18

8-1

15-3

19

8-2

24-1

7-5

25

22

21

7-6

24-2

19-1

26

19-2

7-4

30

23

19-3

28

20

7-3

7-2

29

7-1

32

20-1

24

27

31

24-3

33

34

41-2

38

42-2

39

41

27-2

7-7

41-3

24-4

7-8

42

40

7-14

7-9

35

37

36

7-12

7-11

7-13

7-10

47

49

51-1

48

51-2

51-3

45

13-8

57

12-4

12-7

12-9

13-12-trans

13-12-cis

13-9

12-5

13-10

15-6

66

56

46

52

58

59

53

12-8

13-11

44

12-6

15-5

15-4

15-7

65-1

54

50

43

63

65-2

7-16

61

13-13-cis

13-13-trans

13-14-cis

13-14-trans

7-17

15-8

62

55

7-15or pharmaceutically acceptable salts thereof.

The compounds described above may be prepared according to knownmethods, including those described in U.S. Pat. No. 7,829,552, which isincorporated herein by reference in its entirety. Additional TRβagonists are described in U.S. Pat. No. 7,514,419; U.S. ApplicationPublication No. 2009/002895; U.S. Application Publication No.2010/0081634; U.S. Application Publication No. 2012/0046364; and PCTApplication Publication No. WO 2011/038207, all of which areincorporated herein by reference in their entirety.

Pharmaceutical Compositions

The compounds useful as described above can be formulated intopharmaceutical compositions for use in treatment of the conditionsdescribed herein. Standard pharmaceutical formulation techniques areused, such as those disclosed in Remington's The Science and Practice ofPharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporatedherein by reference in its entirety. Accordingly, some embodimentsinclude pharmaceutical compositions comprising: (a) a safe andtherapeutically effective amount of a compound described herein, orpharmaceutically acceptable salts thereof; and (b) a pharmaceuticallyacceptable carrier, diluent, excipient or combination thereof.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, diluents,emulsifiers, binders, buffers, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents and thelike, or any other such compound as is known by those of skill in theart to be useful in preparing pharmaceutical formulations. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions. In addition, various adjuvantssuch as are commonly used in the art may be included. These and othersuch compounds are described in the literature, e.g., in the MerckIndex, Merck & Company, Rahway, N.J. Considerations for the inclusion ofvarious components in pharmaceutical compositions are described, e.g.,in Gilman et al. (Eds.) (1990); Goodman and Gilman's: ThePharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

Some examples of substances, which can serve aspharmaceutically-acceptable carriers or components thereof, are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such as sodium lauryl sulfate; coloringagents; flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is determined by the way thecompound is to be administered.

The compositions described herein are preferably provided in unit dosageform. As used herein, a “unit dosage form” is a composition containingan amount of a compound that is suitable for administration to asubject, in a single dose, according to good medical practice. Thepreparation of a single or unit dosage form however, does not imply thatthe dosage form is administered once per day or once per course oftherapy. A unit dosage form may comprise a single daily dose or afractional sub-dose wherein several unit dosage forms are to beadministered over the course of a day in order to complete a daily dose.According to the present disclosure, a unit dosage form may be givenmore or less often that once daily, and may be administered more thanonce during a course of therapy. Such dosage forms may be administeredin any manner consistent with their formulation, including orally,parenterally, and may be administered as an infusion over a period oftime (e.g., from about 30 minutes to about 2-6 hours). While singleadministrations are specifically contemplated, the compositionsadministered according to the methods described herein may also beadministered as a continuous infusion or via an implantable infusionpump.

The methods as described herein may utilize any of a variety of suitableforms for a variety of routes for administration, for example, for oral,nasal, rectal, topical (including transdermal), ocular, intracerebral,intracranial, intrathecal, intra-arterial, intravenous, intramuscular,or other parental routes of administration. The skilled artisan willappreciate that oral and nasal compositions include compositions thatare administered by inhalation, and made using available methodologies.Depending upon the particular route of administration desired, a varietyof pharmaceutically-acceptable carriers well-known in the art may beused. Pharmaceutically-acceptable carriers include, for example, solidor liquid fillers, diluents, hydrotropes, surface-active agents, andencapsulating substances. Optional pharmaceutically-active materials maybe included, which do not substantially interfere with the activity ofthe compound. The amount of carrier employed in conjunction with thecompound is sufficient to provide a practical quantity of material foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods describedherein are described in the following references, all incorporated byreference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10(Banker & Rhodes, editors, 2002); Lieberman et al., PharmaceuticalDosage Forms: Tablets (1989); and Ansel, Introduction to PharmaceuticalDosage Forms 8th Edition (2004).

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. Tablets can be compressed,tablet triturates, enteric-coated, sugar-coated, film-coated, ormultiple-compressed, containing suitable binders, lubricants, diluents,disintegrating agents, coloring agents, flavoring agents, flow-inducingagents, and melting agents. Liquid oral dosage forms include aqueoussolutions, emulsions, suspensions, solutions and/or suspensionsreconstituted from non-effervescent granules, and effervescentpreparations reconstituted from effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, melting agents, coloring agents and flavoringagents.

The pharmaceutically-acceptable carriers suitable for the preparation ofunit dosage forms for peroral administration is well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmellose; lubricants such as magnesium stearate, stearic acid,microcrystalline cellulose, carboxymethyl cellulose, and talc. Tabletsmay also comprise solubilizers or emulsifiers, such as poloxamers,cremophor/Kolliphor®/Lutrol®, methylcellulose,hydroxypropylmethylcellulose, or others as are known in the art.Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which can be readily made by a person skilled in theart.

Peroral (PO) compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Compositions described herein may optionally include other drug actives.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

A liquid composition, which is formulated for topical ophthalmic use, isformulated such that it can be administered topically to the eye. Thecomfort may be maximized as much as possible, although sometimesformulation considerations (e.g. drug stability) may necessitate lessthan optimal comfort. In the case that comfort cannot be maximized, theliquid may be formulated such that the liquid is tolerable to thepatient for topical ophthalmic use. Additionally, an ophthalmicallyacceptable liquid may either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions may preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositionsdisclosed herein include, but are not limited to, benzalkonium chloride,PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations disclosed herein. These vehicles include, but are notlimited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose,poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purifiedwater.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. For manycompositions, the pH will be between 4 and 9. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

Ophthalmically acceptable antioxidants include, but are not limited to,sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components, which may be included in the ophthalmicpreparations, are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

For topical use, including for transdermal administration, creams,ointments, gels, solutions or suspensions, etc., containing the compounddisclosed herein are employed. Topical formulations may generally becomprised of a pharmaceutical carrier, co-solvent, emulsifier,penetration enhancer, preservative system, and emollient.

For intravenous administration, the compounds and compositions describedherein may be dissolved or dispersed in a pharmaceutically acceptablediluent, such as a saline or dextrose solution. Suitable excipients maybe included to achieve the desired pH, including but not limited toNaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In variousembodiments, the pH of the final composition ranges from 2 to 8, orpreferably from 4 to 7. Antioxidant excipients may include sodiumbisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate,thiourea, and EDTA. Other non-limiting examples of suitable excipientsfound in the final intravenous composition may include sodium orpotassium phosphates, citric acid, tartaric acid, gelatin, andcarbohydrates such as dextrose, mannitol, and dextran. Furtheracceptable excipients are described in Powell, et al., Compendium ofExcipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998,52 238-311 and Nema et al., Excipients and Their Role in ApprovedInjectable Products: Current Usage and Future Directions, PDA J. Pharm.Sci. Tech. 2011, 65 287-332, both of which are incorporated herein byreference in their entirety. Antimicrobial agents may also be includedto achieve a bacteriostatic or fungistatic solution, including but notlimited to phenylmercuric nitrate, thimerosal, benzethonium chloride,benzalkonium chloride, phenol, cresol, and chlorobutanol.

The compositions for intravenous administration may be provided tocaregivers in the form of one more solids that are reconstituted with asuitable diluent such as sterile water, saline or dextrose in watershortly prior to administration. In other embodiments, the compositionsare provided in solution ready to administer parenterally. In stillother embodiments, the compositions are provided in a solution that isfurther diluted prior to administration. In embodiments that includeadministering a combination of a compound described herein and anotheragent, the combination may be provided to caregivers as a mixture, orthe caregivers may mix the two agents prior to administration, or thetwo agents may be administered separately.

The actual unit dose of the active compounds described herein depends onthe specific compound, and on the condition to be treated. In someembodiments, the dose may be from about 0.01 mg/kg to about 120 mg/kg ormore of body weight, from about 0.05 mg/kg or less to about 70 mg/kg,from about 0.1 mg/kg to about 50 mg/kg of body weight, from about 1.0mg/kg to about 10 mg/kg of body weight, from about 5.0 mg/kg to about 10mg/kg of body weight, or from about 10.0 mg/kg to about 20.0 mg/kg ofbody weight. In some embodiments, the dose may be less than 100 mg/kg,90 mg/kg, 80 mg/kg, 70 mg/kg, 60 mg/kg, 50 mg/kg, 40 mg/kg, 30 mg/kg, 25mg/kg, 20 mg/kg, 10 mg/kg, 7.5 mg/kg, 6 mg/kg, 5 mg/kg, 4 mg/kg, 3mg/kg, 2.5 mg/kg, 1 mg/kg, 0.5 mg/kg, 0.1 mg/kg, 0.05 mg/kg or 0.005mg/kg of body weight. In some embodiments, the actual unit dose is 0.05,0.07, 0.1, 0.3, 1.0, 3.0, 5.0, 10.0 or 25.0 mg/kg of body weight. Thus,for administration to a 70 kg person, the dosage range would be fromabout 0.1 mg to 70 mg, from about 1 mg to about 50 mg, from about 0.5 mgto about 10 mg, from about 1 mg to about 10 mg, from about 2.5 mg toabout 30 mg, from about 35 mg or less to about 700 mg or more, fromabout 7 mg to about 600 mg, from about 10 mg to about 500 mg, or fromabout 20 mg to about 300 mg, or from about 200 mg to about 2000 mg. Insome embodiments, the actual unit dose is 5 mg. In some embodiments theactual unit dose is 10 mg. In some embodiments, the actual unit dose is25 mg. In some embodiments, the actual unit dose is 250 mg or less. Insome embodiments, the actual unit dose is 100 mg or less. In someembodiments, the actual unit dose is 70 mg or less.

Said compounds may also be incorporated into formulations for deliveryoutside the systemic circulation. Such formulations may includeenteric-coated capsules, tablets, soft-gels, spray dried powders,polymer matrices, hydrogels, enteric-coated solids, crystalline solids,amorphous solids, glassy solids, coated micronized particles, liquids,nebulized liquids, aerosols, or microcapsules.

Methods of Administration

The compositions described above may be administered through anysuitable route of administration, for example, by injection, such assubcutaneously, intramuscularly, intraperitoneally, intravenously, orintraarterially; topically, such as by cream, lotion, or patch; orally,such as by a pill, dissolved liquid, oral suspension, buccal film, ormouthrinse; nasally, such as by a nasal aerosol, powder, or spray; orocularly, such as by an eye drop). In some embodiments, the compositionmay be administered one, twice, three times, our four times per day. Inother embodiments, the composition may be administered once, twice, orthree times per week. In other embodiments, the composition isadministered every other day, every three days, or every four days. Inother embodiments, the composition every other week, every three weeks,or every four weeks. In other embodiments, the composition isadministered once per month or twice per month.

In some embodiments, an initial loading dose is administered which ishigher than subsequent doses (maintenance doses). The dosage form ormode of administration of a maintenance dose may be different from thatused for the loading dose. In any of the embodiments disclosed herein, amaintenance dose may comprise administration of the unit dosage form onany dosing schedule contemplated herein, including but not limited to,monthly or multiple times per month, biweekly or multiple times each twoweeks, weekly or multiple times per week, daily or multiple times perday. It is contemplated within the present disclosure that dosingholidays may be incorporated into the dosing period of the maintenancedose. Such dosing holidays may occur immediately after theadministration of the loading dose or at any time during the period ofadministration of the maintenance dose. In some embodiments, the loadingdose is 300 mg or less; 250 mg or less, 200 mg or less, 150 mg or less,or 100 mg or less. In some embodiments, the maintenance dose is 300 mgor less; 200 mg or less, 100 mg or less, 50 mg or less, 25 mg or less,10 mg or less, 5 mg or less, or 1 mg or less.

Methods of Treatment

Some embodiments according to the methods and compositions of thepresent disclosure relate to a method for the reduction or prevention ofthe deposition of extracellular matrix proteins, comprisingadministering an effective amount of a compound described herein to asubject in need thereof. In some embodiments, said deposition ofextracellular matrix proteins may comprise abnormal or excessivedeposition of said proteins. In some embodiments, said extracellularmatrix proteins may comprise one or more of collagen, keratin, elastin,or fibrin. In some embodiments, said extracellular matrix proteins maycomprise collagen. In some embodiments, said extracellular matrixproteins may comprise Type I collagen. In some embodiments, saidextracellular matrix proteins may comprise Collagen Type Ia. In someembodiments, said extracellular matrix proteins may comprise Type IIcollagen. Some embodiments according to the compositions and methods ofthe present disclosure relate to a method for the treatment of afibrosis or its symptoms or sequelae, comprising administering aneffective amount of a compound described herein to a subject in needthereof.

In some embodiments, the compounds and compositions comprising thecompounds described herein can be used to treat a variety of conditionsarising from fibrosis or inflammation, and specifically including thoseassociated with abnormal collagen deposition. Example conditions includeglycogen storage disease type III (GSD III), glycogen storage diseasetype VI (GSD VI), glycogen storage disease type IX (GSD IX),non-alcoholic steatohepatitis (NASH), cirrhosis, hepatitis, scleroderma,alcoholic fatty liver disease, atherosclerosis, asthma, cardiacfibrosis, organ transplant fibrosis, muscle fibrosis, pancreaticfibrosis, bone-marrow fibrosis, liver fibrosis, cirrhosis of liver andgallbladder, fibrosis of the spleen, pulmonary fibrosis, idiopathicpulmonary fibrosis, diffuse parenchymal lung disease, idiopathicinterstitial fibrosis, diffuse interstitial fibrosis, interstitialpneumonitis, desquamative interstitial pneumonia, respiratorybronchiolitis, interstitial lung disease, chronic interstitial lungdisease, acute interstitial pneumonitis, hypersensitivity pneumonitis,nonspecific interstitial pneumonia, cryptogenic organizing pneumonia,lymphocytic interstitial pneumonia, pneumoconiosis, silicosis,emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis,cardiac fibrosis, atrial fibrosis, endomyocardial fibrosis, renalfibrosis, chronic kidney disease, Type II diabetes, maculardegeneration, keloid lesions, hypertrophic scar, nephrogenic systemicfibrosis, injection fibrosis, complications of surgery, fibrotic chronicallograft vasculopathy and/or chronic rejection in transplanted organs,fibrosis associated with ischemic reperfusion injury, post-vasectomypain syndrome, fibrosis associated with rheumatoid arthritis,arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixedconnective tissue disease, fibrous proliferative lesions of the oralcavity, fibrosing intestinal strictures, Crohn's disease, glialscarring, leptomeningeal fibrosis, meningitis, systemic lupuserythematosus, fibrosis due to radiation exposure, fibrosis due tomammary cystic rupture, myelofibrosis, retroperitoneal fibrosis,progressive massive fibrosis, or symptoms or sequelae thereof, or otherdiseases or conditions resulting in the excessive deposition ofextracellular matrix components, such as collagen.

In some embodiments the methods of the present disclosure comprisemethods for the treatment, amelioration, or prevention of a fibroticcondition. In some embodiments, said fibrotic condition may be secondaryto another condition. In some embodiments, said fibrotic condition orprimary condition may further comprise chronic inflammation of an organ,tissue, spatial region, or fluid-connected area of the body of asubject. In some embodiments, said inflammation may comprise activationof one or more TGF-beta dependent signaling pathways. In someembodiments, said TGF-β dependent signaling pathways may comprise one ormore elements responsive to T3 or T4. In some embodiments, said fibroticcondition may comprise abnormal or excessive deposition of one or moreof collagen, keratin, or elastin. In some embodiments, said fibroticcondition may comprise abnormal or excessive deposition of collagen. Insome embodiments, said fibrotic condition may comprise abnormal orexcessive deposition of Type I collagen. In some embodiments, saidfibrotic condition may comprise abnormal or excessive deposition ofCollagen Type Ia. In some embodiments, said fibrotic condition maycomprise abnormal or excessive deposition of Type III collagen. In someembodiments said fibrotic condition may comprise one or more of glycogenstorage disease type III (GSD III), glycogen storage disease type VI(GSD VI), glycogen storage disease type IX (GSD IX), non-alcoholicsteatohepatitis (NASH), cirrhosis, hepatitis, scleroderma, alcoholicfatty liver disease, atherosclerosis, asthma, cardiac fibrosis, organtransplant fibrosis, muscle fibrosis, pancreatic fibrosis, bone-marrowfibrosis, liver fibrosis, cirrhosis of liver and gallbladder, fibrosisof the spleen, scleroderma, pulmonary fibrosis, idiopathic pulmonaryfibrosis, diffuse parenchymal lung disease, idiopathic interstitialfibrosis, diffuse interstitial fibrosis, interstitial pneumonitis,desquamative interstitial pneumonia, respiratory bronchiolitis,interstitial lung disease, chronic interstitial lung disease, acuteinterstitial pneumonitis, hypersensitivity pneumonitis, nonspecificinterstitial pneumonia, cryptogenic organizing pneumonia, lymphocyticinterstitial pneumonia, pneumoconiosis, silicosis, emphysema,interstitial fibrosis, sarcoidosis, mediastinal fibrosis, cardiacfibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis,chronic kidney disease, Type II diabetes, macular degeneration, keloidlesions, hypertrophic scar, nephrogenic systemic fibrosis, injectionfibrosis, complications of surgery, fibrotic chronic allograftvasculopathy and/or chronic rejection in transplanted organs, fibrosisassociated with ischemic reperfusion injury, post-vasectomy painsyndrome, fibrosis associated with rheumatoid arthritis, arthrofibrosis,Dupuytren's disease, dermatomyositis-polymyositis, mixed connectivetissue disease, fibrous proliferative lesions of the oral cavity,fibrosing intestinal strictures, Crohn's disease, glial scarring,leptomeningeal fibrosis, meningitis, systemic lupus erythematosus,fibrosis due to radiation exposure, fibrosis due to mammary cysticrupture, myelofibrosis, retroperitoneal fibrosis, progressive massivefibrosis. In some embodiments, said fibrotic condition may comprise oneor more of GSD III, GSD IX, Non Alcoholic Steatohepatitis, cirrhosis ofthe liver and/or pancreas, scleroderma, idiopathic pulmonary fibrosis,psoriasis, alcoholic fatty liver disease, Dupuytren's disease, and/orany combination thereof.

According to the methods and compositions of the present disclosure,thyroid receptor agonists such as those disclosed herein, and especiallyincluding Compounds 1-4, may be administered to a subject for thetreatment, amelioration, prevention, or cure of a fibrotic condition, ora condition for which fibrosis is a symptom or sequela. According to themethods and composition as disclosed herein, said fibrotic condition orcondition having fibrosis as a sequela may further comprise chronicinflammation. According to the methods and compositions as disclosedherein, said fibrotic condition or condition having fibrosis as asequela may further comprise activation of one or more TGF-β dependentsignaling pathways. According to the methods and compositions asdisclosed herein, said fibrotic condition or condition having fibrosisas a sequela may further comprise activation and/or repression of one ormore Thyroid Receptor Beta (TRβ) dependent signaling pathways. Accordingto the methods and compositions as disclosed herein, said fibroticcondition or condition having fibrosis as a sequela may further comprisethe involvement of signaling pathways responsive to triiodothyronine(T3), thyroxine (T4), any combination thereof, or mimetics thereof.According to the methods and compositions as disclosed herein, saidfibrotic condition or condition having fibrosis as a sequela may furthercomprise the involvement of receptors responsive to T3, T4, anycombination thereof, or mimetics thereof. In some embodiments accordingto the methods and compositions disclosed herein, said fibroticcondition or condition having fibrosis as a sequela may comprise theinvolvement of TRβ. In some embodiments according to the methods andcompositions disclosed herein, said fibrotic condition or conditionhaving fibrosis as a sequela may comprise one or more conditions whichare prevented, ameliorated, or cured by the administration of one ormore agonists of TRβ. In some embodiments according to the methods andcompositions disclosed herein, said fibrotic condition or conditionhaving fibrosis as a sequela may comprise one or more conditions whichare prevented, ameliorated, or cured by the administration of one ormore of Compounds 1-4. In some embodiments, said one or more agonists ofTRβ, or said one or more of Compounds 1-4, may be coadministered withone or more active drug compounds and/or one or more excipients. In someembodiments, said one or more agonists of TRβ, or said one or more ofCompounds 1-4, may be administered prior to, during, or after a surgicalintervention, phototherapy, or ultrasound therapy. In some embodiments,said one or more agonists of TRβ, or said one or more of Compounds 1-4,may be coadministered with one or more of Pirfenidone, nintedanib,and/or a fibroblast growth factor receptor antagonist, and/or acollagenase, such as Clostridium histolyticum collagenase.

In some embodiments, the compositions and methods described hereinprovide compositions and methods for the treatment, amelioration,prevention or cure of collagen deposition. In some embodiments, saidcollagen deposition comprises and abnormal or excessive deposition ofcollagen. In some embodiments, said collagen deposition may compriseabnormal or excessive deposition of Type I collagen. In someembodiments, said collagen deposition may comprise abnormal or excessivedeposition of Collagen Type Ia. In some embodiments, said collagendeposition may comprise abnormal or excessive deposition of Type IIIcollagen. According to the methods and compositions as disclosed herein,said collagen deposition may further comprise the involvement ofreceptors responsive to T3, T4, any combination thereof, or mimeticsthereof. In some embodiments according to the methods and compositionsdisclosed herein, said collagen deposition may comprise the involvementof TRβ. In some embodiments according to the methods and compositionsdisclosed herein, said collagen deposition may be prevented,ameliorated, or cured by the administration of one or more agonists ofTRβ. In some embodiments according to the methods and compositionsdisclosed herein, said collagen deposition may be prevented,ameliorated, or cured by the administration of one or more of Compounds1-4. In some embodiments, said one or more agonists of TRβ, or said oneor more of Compounds 1-4, may be coadministered with one or more activedrug compounds and/or one or more excipients. In some embodiments, saidone or more agonists of TRβ, or said one or more of Compounds 1-4, maybe administered prior to, during, or after a surgical intervention,phototherapy, or ultrasound therapy. In some embodiments, said one ormore agonists of TRβ, or said one or more of Compounds 1-4, may becoadministered with one or more of Pirfenidone, nintedanib, and/or afibroblast growth factor receptor antagonist, and/or a collagenase, suchas Clostridium histolyticum collagenase.

In some embodiments, administration of compounds 1-4, of compound 2, orof any of the compounds or compositions as disclosed herein results in areduction in the expression of the Cola1, Col3a1, αSMA, and/or Galectin1genes or any combination or product thereof in the subject to which saidcompound or composition is administered. In some embodiments,administration of compounds 1-4, of compound 2, or of any of thecompounds or compositions as disclosed herein results in a reduction inthe degree of fibrosis observable by histology, histochemistry,immunohistochemistry, or the like, and/or reduction s in the amount,accumulation, or distribution of type I collagen and/or hydroxyprolineor any combination thereof in the subject to which said compound orcomposition is administered. In some embodiments, administration ofcompounds 1-4, of compound 2, or of any of the compounds or compositionsas disclosed herein results in a reduction in total serum lipids, totalserum cholesterol, total serum triglycerides, total liver lipids, totalliver cholesterol, total liver triglycerides, or any combinationthereof.

The methods described herein are further illustrated by the followingexamples.

Example 1

DIO-NASH mice were acclimatized for 3 weeks, with pre-treatment liverbiopsy samples collected prior to acclimatization. Mice were randomlyassigned to one of five dosing groups, with 12 mice per group. Assigneddosages were: Compound 2 (low): 3 mg/kg; Compound 2 (high): 10 mg/kg;Compound 1: 10 mg/kg; and Elafibranor (30 mg·kg). One group was mocktreated with vehicle only as a control. Dosage forms were administeredorally once per day. After 8 weeks, animals were sacrificed and liversamples were taken. Liver samples were assayed for total liverhydroxyproline, and subjected to immunohistochemical observation forfibrosis stage as well as the extent of Cola1 (Collagen Type Ia)staining. As shown in FIG. 1, Compound 2-treated animals show lowertotal liver hydroxyproline levels than control-treated or mock-treatedanimals. Since hydroxyproline is a significant component of collagen,and collagen is the most significant source of hydroxyproline in animaltissues, levels of hydroxyproline provide a reliable proxy for thepresence of collagen in a sample.

Terminal liver biopsy samples were also subjected to histochemicalstaining and immunohistochemical staining. Representative images ofliver stained with Picro-Sirius Red (to visualize collagen I and IIIdeposition, red stain) at the end of the treatment period following 8weeks of treatment with vehicle, low dose Compound 2, high dose Compound2, Compound 1, or elafibranor are shown in FIG. 2. As shown in FIG. 5,total liver collagen (mg/liver) 1 and 3 was determined by morphometryfollowing Picro-Sirius Red staining. Liver sections fromCompound-1-treated animals showed lower PSR staining than those frommock-treated animals; liver sections from Compound 2-treated animalsshowed lower PSR staining than control-treated or mock-treated animals.Representative images of liver stained with anti-type I collagen(colla1) (Southern Biotech, Cat. 131001) at the end of the treatmentperiod following 8 weeks of treatment with vehicle, low dose Compound 2,high dose Compound 2, Compound 1, or elafibranor are shown in FIG. 3.The extent of ColA1 content was calculated as the total liver ColA1staining in terminal liver biopsy samples. As shown in FIG. 4, Compound2-treated animals show lower total liver ColA1 content thancontrol-treated or mock-treated animals.

Fibrosis scores were also calculated based on observation of terminalliver biopsy samples. Additionally, a higher proportion of animalstreated with Compound 1 or Compound 2 showed a reduction in fibrosisscore post-treatment than did mock treated animals. No Compound2-treated animals showed increases in their fibrosis scorepost-treatment.

Example 2

Pulmonary fibrosis is induced in healthy male Dunkin-Hartley guinea pigsby administering bleomycin intratracheally. Control subjects aredeveloped by intratracheal administration of saline solution. After theestablishment of pulmonary fibrosis in the bleomycin treated animals,test articles comprising any one of Compounds 1-4, or any other compounddisclosed herein, are administered to each subject as appropriate forits formulation, daily or as appropriate, for 6-10 weeks. Unilaterallung biopsies are taken prior to the first administration of the testarticles and again after sacrifice following the last administration ofthe test articles. Biopsy samples are analyzed as described in ExampleI, with the addition of immunohistochemical staining for type IIIcollagen. Lungs from animals treated with the compounds disclosedherein, especially those animals treated with Compound 2, show reducedlevels of hydroxyproline, decreased Collagen III staining, and decreasedfibrosis score relative to the levels shown prior to the administrationof the test articles. Mock treated animals show little or no reductionin fibrosis, hydroxyproline content, or Collagen III content.

Example 2

Palmar fascia fibrosis is induced in nude mice by introducingfibroblasts from fibrotic cords of Dupuytren's disease patients asdescribed in Stish, L. et al., BMC Musculoskelet. Disord. 16: 138-148(2015) which is hereby incorporated by reference with respect to itsdescription of the establishment of an animal model system for the studyof palmar fascia fibrosis. After the establishment of palmar fasciafibrosis in the fibroblast treated animals, test articles comprising anyone of Compounds 1-4, or any other compound disclosed herein, areadministered to each subject as appropriate for its formulation, dailyor as appropriate, for 6-10 weeks. Unilateral forepaw biopsies are takenprior to the first administration of the test articles and again aftersacrifice following the last administration of the test articles. Biopsysamples are analyzed as described in Example 1, with the addition ofimmunohistochemical staining for type I collagen. Palmar fascia fromanimals treated with the compounds disclosed herein, especially thoseanimals treated with Compound 2, show reduced levels of hydroxyproline,decreased Collagen III staining, and decreased fibrosis score relativeto the levels shown prior to the administration of the test articles.Mock treated animals show little or no reduction in fibrosis,hydroxyproline content, or Collagen III content.

Example 3

Hypertrophic skin lesions are induced in Sprague-Dawley Rats bysubcutaneous injection of capsaicin as described in Wallengren, J. etal., Skin Pharm. Appl. Skin Physiol. 15(3):154-165 (2002), which ishereby incorporated by reference with respect to its description of theinduction of hypertrophic skin lesions in rats; or in C57BL or otherappropriate strain mice by subcutaneous administration of CCl₄ and/orbleomycin, as described in Alonso-Merino et al., Proc. Nat. Acad. Sci.113(24):E3451-60 (2016), which is incorporated herein for its disclosureof the induction of fibrotic skin lesions in mice. After theestablishment of hypertrophic skin lesions in the capsaicin, CCl₄ and/orbleomycin treated animals, test articles comprising any one of Compounds1-4, or any other compound disclosed herein, are administered to eachsubject animal as appropriate for its formulation, daily or asappropriate, for 6-10 weeks. Skin biopsies from the injection site aretaken prior to the first administration of the test articles and againafter sacrifice following the last administration of the test articles.Biopsy samples are analyzed as described in Example I, with the additionof immunohistochemical staining for type III collagen. Injection siteskin samples from animals treated with the compounds disclosed herein,especially those animals treated with Compound 2, show reduced levels ofhydroxyproline, decreased Collagen III staining, and decreased fibrosisscore relative to the levels shown prior to the administration of thetest articles. Mock treated animals show little or no reduction infibrosis, hydroxyproline content, or Collagen III content.

Example 4

Glucose-6-phosphatase-α deficient mice that manifest GSD-3- like hepaticsymptoms, including hypercholesterolemia and hyperlipidemia (Agl−/−, seee.g. Liu, K. M. et al., Mol. Genet. Metabol. 111(4):467-76 (2014)) aretreated with test articles comprising any one of Compounds 1-4, or anyother compound disclosed herein, administered to each subject asappropriate for its formulation, daily or as appropriate, for 6-10weeks. Liver biopsies are taken prior to the first administration of thetest articles and again after sacrifice following the lastadministration of the test articles. Biopsy samples are analyzed asdescribed in Example I. Liver samples from animals treated with thecompounds disclosed herein, especially those animals treated withCompound 2, show reduced levels of hydroxyproline, decreased Collagen Istaining, and decreased fibrosis score relative to the levels shownprior to the administration of the test articles. Mock treated animalsshow little or no reduction in fibrosis, hydroxyproline content, orCollagen I content.

Example 5

Phosphorylase kinase deficient mice that manifest GSD-8/9- like hepaticsymptoms, including hypercholesterolemia and hyperlipidemia (PhKc−/−,see, e.g., Varsanyi, M. et al., Biochem. Genet. 18(3-4):247-61 (1980)),are treated with test articles comprising any one of Compounds 1-4, orany other compound disclosed herein, administered to each subject asappropriate for its formulation, daily or as appropriate, for 6-10weeks. Liver biopsies are taken prior to the first administration of thetest articles and again after sacrifice following the lastadministration of the test articles. Biopsy samples are analyzed asdescribed in Example I. Liver samples from animals treated with thecompounds disclosed herein, especially those animals treated withCompound 2, show reduced levels of hydroxyproline, decreased Collagen Istaining, and decreased fibrosis score relative to the levels shownprior to the administration of the test articles. Mock treated animalsshow little or no reduction in fibrosis, hydroxyproline content, orCollagen I content.

Example 6

Compound 2 was evaluated in a diet-induced NASH mouse model (See, e.g.,Hansen, H. et al., Drug Discovery Today 22(17):1701-1718 (2017) which ishereby incorporated by reference with respect to its disclosure ofdiet-induced, genetic, chemical, and other NASH mouse models).Diet-driven NASH in this model does not rely on chemical/toxin effectsto generate steatohepatitis/fibrosis. Animals were biopsied pre-study,and only animals with NASH and fibrosis were selected for study.Selected animals were acclimatized and randomized, with experimentalgroups of 11-12 animals per cohort receiving oral dosing of compound 2according to the following schedules: Daily dosing for 8 weeks; or dailydosing for week 0-1 followed by weekly dosing for weeks 2-8. At week 8,animals were sacrificed and tissues analyzed. Plasma enzymes (P-ALT(alanine aminotransferase) and P-AST (aspartate aminotransferase)),total plasma triglycerides, and total plasma cholesterol were measured,and terminal necropsy of each liver was carried out, assaying totalliver biochemistry including total liver triglycerides, and total livercholesterol, as well as histological evaluation of NAFLD activity score(done pre- and post-treatment), fibrosis stage (also done pre- andpost-treatment), steatosis, Colla1 level, and galactin-3 level. Tissuesamples were preserved for characterization using RNAseq; RNAseq wasused to determine expression levels for genes showing differentialexpression in compound 2-treated vs. vehicle treated animals and/orgenes known to be implicated in fibrosis. Significant reductions inliver triglycerides and cholesterol were observed in treatment groupsrelative to untreated controls. As shown in FIG. 6, total lipid contentin the liver was reduced by approximately 80%, with similar reductionsin plasma lipids and significant improvements in NAS scores. Nosignificant toxicity was observed.

As shown in FIG. 7, significant reductions in fibrosis, type 1 collagendeposition, and hydroxyproline (50.2%, 60.2%, and 46.3%, respectively)were also seen relative to pre-treatment samples. Post-treatment,expression of pro-fibrotic genes Colla1, Col3a1, αSMA, and Galectin 1were reduced by 36.3%, 27.1%, 37%, and 64.7%, respectively (FIG. 8),confirming the results observed by histology. Thus, 8-week dosing withcompound 2 resulted in marked improvements in histological, biochemical,and genetic markers related to steatosis, fibrosis, and non-alcoholicsteatohepatitis in a diet-induced NASH model.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to plural as isappropriate to the context and/or application. The varioussingular/plural permutations can be expressly set forth herein for sakeof clarity.

It will be understood by those within the art that, in general, termsused herein, and especially in the appended claims (for example, bodiesof the appended claims) are generally intended as “open” terms (forexample, the term “including” should be interpreted as “including butnot limited to,” the term “having” should be interpreted as “having atleast,” the term “includes” should be interpreted as “includes but isnot limited to,” etc.). It will be further understood by those withinthe art that if a specific number of an introduced claim recitation isintended, such an intent will be explicitly recited in the claim, and inthe absence of such recitation no such intent is present. For example,as an aid to understanding, the following appended claims can containusage of the introductory phrases “at least one” and “one or more” tointroduce claim recitations. However, the use of such phrases should notbe construed to imply that the introduction of a claim recitation by theindefinite articles “a” or “an” limits any particular claim containingsuch introduced claim recitation to embodiments containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (for example, “a” and/or “an” should be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations. In addition, evenif a specific number of an introduced claim recitation is explicitlyrecited, those skilled in the art will recognize that such recitationshould be interpreted to mean at least the recited number (for example,the bare recitation of “two recitations,” without other modifiers, meansat least two recitations, or two or more recitations). Furthermore, inthose instances where a convention analogous to “at least one of A, B,and C, etc.” is used, in general such a construction is intended in thesense one having skill in the art would understand the convention (forexample, “a system having at least one of A, B, and C” would include butnot be limited to systems that have A alone, B alone, C alone, A and Btogether, A and C together, B and C together, and/or A, B, and Ctogether, etc.). In those instances where a convention analogous to “atleast one of A, B, or C, etc.” is used, in general such a constructionis intended in the sense one having skill in the art would understandthe convention (for example, “a system having at least one of A, B, orC” would include but not be limited to systems that have A alone, Balone, C alone, A and B together, A and C together, B and C together,and/or A, B, and C together, etc.). It will be further understood bythose within the art that virtually any disjunctive word and/or phrasepresenting two or more alternative terms, whether in the description,claims, or drawings, should be understood to contemplate thepossibilities of including one of the terms, either of the terms, orboth terms. For example, the phrase “A or B” will be understood toinclude the possibilities of “A” or “B” or “A and B.”

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and allpurposes, such as in terms of providing a written description, allranges disclosed herein also encompass any and all possible sub-rangesand combinations of sub-ranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into sub-ranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember. Thus, for example, a group having 1-3 articles refers to groupshaving 1, 2, or 3 articles. Similarly, a group having 1-5 articlesrefers to groups having 1, 2, 3, 4, or 5 articles, and so forth.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopeand spirit being indicated by the following claims.

What is claimed is:
 1. A method of treating fibrosis, a fibroticcondition or a fibrotic symptom in a subject in need thereof comprisingadministering to said subject in need thereof at least one compound ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein: G is selectedfrom the group consisting of —O—, —S—, —S(═O)—, —S(═O)₂—, —Se—, —CH₂—,—CF₂—, —CHF—, —C(O)—, —CH(OH)—, —CH(C₁-C₄ alkyl)-, —CH(C₁-C₄ alkoxy)-,—C(═CH₂)—, —NH—, and —N(C₁-C₄ alkyl)-; T is selected from the groupconsisting of —(CR^(a) ₂)_(k)—, —CR^(b)═CR^(b)—(CR^(a) ₂)_(n)—, —(CR^(a)₂)_(n)—CR^(b)═CR^(b)—, —(CR^(a) ₂)—CR^(b)═CR^(b)—(CR^(a) ₂)—, —O(CR^(b)₂)(CR^(a) ₂)_(n)—, —S(CR^(b) ₂)(CR^(a) ₂)n-, N(R^(c))(CR^(b) ₂)(CR^(a)₂)_(n)—, N(R^(b))C(O)(CR^(a) ₂)_(n), —C(O)(CR^(a) ₂)_(m)—, —(CR^(a)₂)_(m)C(O)—, —(CR^(a) ₂)C(O)(CR^(a) ₂)_(n), —(CR^(a) ₂)_(n)C(O)(CR^(a)₂)—, and —C(O)NH(CR^(b) ₂)(CR^(a) ₂)_(p)—; k is an integer from 1-4; mis an integer from 0-3; n is an integer from 0-2; p is an integer from0-1; each R^(a) is independently selected from the group consisting ofhydrogen, optionally substituted —C₁-C₄ alkyl, halogen, —OH, optionallysubstituted —O—C₁-C₄ alkyl, —OCF₃, optionally substituted —S—C₁-C₄alkyl, —NR^(b)R^(c), optionally substituted —C₂-C₄ alkenyl, andoptionally substituted —C₂-C₄ alkynyl; with the proviso that when oneR^(a) is attached to C through an O, S, or N atom, then the other R^(a)attached to the same C is a hydrogen, or attached via a carbon atom;each R^(b) is independently selected from the group consisting ofhydrogen and optionally substituted —C₁-C₄ alkyl; each R^(c) isindependently selected from the group consisting of hydrogen andoptionally substituted —C₁-C₄ alkyl, optionally substituted —C(O)—C₁-C₄alkyl, and —C(O)H; R¹, and R² are each independently selected from thegroup consisting of halogen, optionally substituted —C₁-C₄ alkyl,optionally substituted —S—C₁-C₃ alkyl, optionally substituted —C₂-C₄alkenyl, optionally substituted —C₂-C₄ alkynyl, —CF₃, —OCF₃, optionallysubstituted-O—C₁-C₃ alkyl, and cyano; R⁶, R⁷, R⁸, and R⁹ are eachindependently selected from the group consisting of are eachindependently selected from the group consisting of hydrogen, halogen,optionally substituted —CC₁-C₄ alkyl, optionally substituted —S—C₁-C₃alkyl, optionally substituted —C₂-C₄ alkenyl, optionally substituted—C₂-C₄ alkynyl, —CF₃, —OCF₃, optionally substituted-O—C₁-C₃ alkyl, andcyano; or R⁶ and T are taken together along with the carbons they areattached to form a ring of 5 to 6 atoms including 0 to 2 heteroatomsindependently selected from —NR^(i)—, —O—, and —S—, with the provisothat when there are 2 heteroatoms in the ring and both heteroatoms aredifferent than nitrogen then both heteroatoms have to be separated by atleast one carbon atom; and X is attached to this ring by a direct bondto a ring carbon, or by —(CR^(a) ₂)— or —C(O)— bonded to a ring carbonor a ring nitrogen; R^(i) is selected from the group consisting ofhydrogen, —C(O)C₁-C₄ alkyl, —C₁-C₄ alkyl, and —C₁-C₄-aryl; R³ and R⁴ areindependently selected from the group consisting of hydrogen, halogen,—CF₃, —OCF₃, cyano, optionally substituted —C₁-C₁₂ alkyl, optionallysubstituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂ alkynyl,—SR^(d), —S(═O)R^(e), —S(═O)₂R^(e), —S(═O)₂NR^(f)R^(g), —C(O)OR^(h),—C(O)R^(e), —N(R^(b))C(O)NR^(f)R^(g), —N(R^(b))S(═O)₂R^(e),—N(R^(b))S(═O)₂NR^(f)R^(g), and —NR^(f)R^(g); each R^(d) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(b) ₂)_(n) aryl, optionallysubstituted —(CR^(b) ₂)_(n) cycloalkyl, optionally substituted —(CR^(b)₂)_(n) heterocycloalkyl, and —C(O)NR^(f)R^(g); each R^(e) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(a) ₂)_(n) aryl, optionallysubstituted —(CR^(a) ₂)_(n) cycloalkyl, and optionally substituted—(CR^(a) ₂)_(n) heterocycloalkyl; R^(f) and R^(g) are each independentlyselected from the group consisting of hydrogen, optionally substituted—C₁-C₁₂ alkyl, optionally substituted —C₂-C₁₂ alkenyl, optionallysubstituted —C₂-C₁₂ alkynyl, optionally substituted —(CR^(b) ₂)_(n)aryl, optionally substituted —(CR^(b) ₂)_(n) cycloalkyl, and optionallysubstituted —(CR^(b) ₂)_(n) heterocycloalkyl, or R^(f) and R^(g) maytogether form an optionally substituted heterocyclic ring, which maycontain a second heterogroup selected from the group consisting of O,NR^(C), and S, wherein said optionally substituted heterocyclic ring maybe substituted with 0-4 substituents selected from the group consistingof optionally substituted —C₁-C₄ alkyl, —OR^(b), oxo, cyano, —CF₃,optionally substituted phenyl, and —C(O)OR^(h); each R^(h) is selectedfrom the group consisting of optionally substituted —C₁-C₁₂ alkyl,optionally substituted —C₂-C₁₂ alkenyl, optionally substituted —C₂-C₁₂alkynyl, optionally substituted —(CR^(b) ₂)_(n) aryl, optionallysubstituted —(CR^(b) ₂)_(n) cycloalkyl, and optionally substituted—(CR^(b) ₂)_(n) heterocycloalkyl; R⁵ is selected from the groupconsisting of —OH, optionally substituted —OC₁-C₆ alkyl, OC(O)R^(e),—OC(O)OR^(h), —F, —NHC(O)R^(e), —NHS(═O)R^(e), —NHS(═O)₂R^(e),—NHC(═S)NH(R^(h)), and —NHC(O)NH(R^(h)); X is P(O)YR¹¹Y′R¹¹; Y and Y′are each independently selected from the group consisting of —O—, and—NR^(v)—; when Y and Y′ are —O—, R¹¹ attached to —O— is independentlyselected from the group consisting of —H, alkyl, optionally substitutedaryl, optionally substituted heterocycloalkyl, optionally substitutedCH₂-heterocycloakyl wherein the cyclic moiety contains a carbonate orthiocarbonate, optionally substituted -alkylaryl, —C(R^(z))₂C(O)NR^(z)₂, —NR^(z)—C(O)—R^(y), —C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y),—C(R^(z))₂OC(O)SR^(y), -alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; when Y and Y′ are —NR^(v)—, then R¹¹ attachedto —NR^(v)— is independently selected from the group consisting of —H,—[C(R^(z))₂]_(q)—COOR^(y), —C(R^(x))₂COOR^(Y),—[C(R^(z))₂]_(q)—C(O)SR^(y), and -cycloalkylene-COOR^(y); when Y is —O—and Y′ is NR^(v), then R¹¹ attached to —O— is independently selectedfrom the group consisting of —H, alkyl, optionally substituted aryl,optionally substituted heterocycloalkyl, optionally substitutedCH₂-heterocycloakyl wherein the cyclic moiety contains a carbonate orthiocarbonate, optionally substituted -alkylaryl, —C(R^(z))₂OC(O)NR^(z)₂, —NR^(z)—C(O)—R^(y), —C(R^(z))₂—OC(O)R^(y), —C(R^(z))₂—O—C(O)OR^(y),—C(R^(z))₂OC(O)SR^(y), -alkyl-S—C(O)R^(y), -alkyl-S—S-alkylhydroxy, and-alkyl-S—S—S-alkylhydroxy; and R¹¹ attached to —NR^(v)— is independentlyselected from the group consisting of H, —[C(R^(z))₂]_(q)—COOR^(y),—C(R^(x))₂COOR^(y), —[C(R^(z))₂]_(q)—C(O)SR^(y), and-cycloalkylene-COOR^(y); or when Y and Y′ are independently selectedfrom —O— and NR^(v), then together R¹¹ and R¹¹ are -alkyl-S—S-alkyl- toform a cyclic group, or together R¹¹ and R¹¹ are the group:

wherein: V, W, and W′ are independently selected from the groupconsisting of hydrogen, optionally substituted alkyl, optionallysubstituted aralkyl, heterocycloalkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, optionally substituted 1-alkenyl,and optionally substituted 1-alkynyl; or together V and Z are connectedvia an additional 3-5 atoms to form a cyclic group containing 5-7 atoms,wherein 0-1 atoms are heteroatoms and the remaining atoms are carbon,substituted with hydroxy, acyloxy, alkylthiocarbonyloxy,alkoxycarbonyloxy, or aryloxycarbonyloxy attached to a carbon atom thatis three atoms from both Y groups attached to the phosphorus; ortogether V and Z are connected via an additional 3-5 atoms to form acyclic group, wherein 0-1 atoms are heteroatoms and the remaining atomsare carbon, that is fused to an aryl group at the beta and gammaposition to the Y attached to the phosphorus; or together V and W areconnected via an additional 3 carbon atoms to form an optionallysubstituted cyclic group containing 6 carbon atoms and substituted withone substituent selected from the group consisting of hydroxy, acyloxy,alkoxycarbonyloxy, alkylthiocarbonyloxy, and aryloxycarbonyloxy,attached to one of said carbon atoms that is three atoms from a Yattached to the phosphorus; or together Z and W are connected via anadditional 3-5 atoms to form a cyclic group, wherein 0-1 atoms areheteroatoms and the remaining atoms are carbon, and V must be aryl,substituted aryl, heteroaryl, or substituted heteroaryl; or together Wand W′ are connected via an additional 2-5 atoms to form a cyclic group,wherein 0-2 atoms are heteroatoms and the remaining atoms are carbon,and V must be aryl, substituted aryl, heteroaryl, or substitutedheteroaryl; Z is selected from the group consisting of —CHR^(z)OH,—CHR^(z)OC(O)R^(y), —CHR^(z)OC(S)R^(y), —CHR^(z)OC(S)OR^(y),—CHR^(z)OC(O)SR^(y), —CHR^(z)OCO₂R^(y), —OR^(z), —SR^(z), —CHR^(z)N₃,—CH₂-aryl, —CH(aryl)OH, —CH(CH═CR^(z) ₂)OH, —CH(C≡CR^(z))OH, —R^(z),—NR^(z) ₂, —OCOR^(y), —OCO₂R^(y), —SCOR^(y), —SCO₂R^(y), —NHCOR^(z),—NHCO₂R^(y), —CH₂NH-aryl, —(CH₂)_(q)—OR^(z), and —(CH₂)_(q)—SR^(z); q isan integer 2 or 3; each R^(z) is selected from the group consisting ofR^(y) and —H; each R^(y) is selected from the group consisting of alkyl,aryl, heterocycloalkyl, and aralkyl; each R^(x) is independentlyselected from the group consisting of —H, and alkyl, or together R^(x)and R^(y) form a cyclic alkyl group; and each R^(v) is selected from thegroup consisting of —H, lower alkyl, acyloxyalkyl,alkoxycarbonyloxyalkyl, and lower acyl.
 2. The method of claim 1 whereinthe compound to be administered comprises one or more of the compoundshaving a structure selected from the group consisting of:

or pharmaceutically acceptable salts thereof.
 3. The method of any ofclaims 1-2 wherein said subject has one or more fibrotic conditionsselected from glycogen storage disease type III (GSD II), glycogenstorage disease type VI (GSD VI), glycogen storage disease type IX (GSDIX), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatitis,scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma,cardiac fibrosis, organ transplant fibrosis, muscle fibrosis, pancreaticfibrosis, bone-marrow fibrosis, liver fibrosis, cirrhosis of liver andgallbladder, fibrosis of the spleen, pulmonary fibrosis, idiopathicpulmonary fibrosis, diffuse parenchymal lung disease, idiopathicinterstitial fibrosis, diffuse interstitial fibrosis, interstitialpneumonitis, desquamative interstitial pneumonia, respiratorybronchiolitis, interstitial lung disease, chronic interstitial lungdisease, acute interstitial pneumonitis, hypersensitivity pneumonitis,nonspecific interstitial pneumonia, cryptogenic organizing pneumonia,lymphocytic interstitial pneumonia, pneumoconiosis, silicosis,emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis,cardiac fibrosis, atrial fibrosis, endomyocardial fibrosis, renalfibrosis, chronic kidney disease, Type II diabetes, maculardegeneration, keloid lesions, hypertrophic scar, nephrogenic systemicfibrosis, injection fibrosis, complications of surgery, fibrotic chronicallograft vasculopathy and/or chronic rejection in transplanted organs,fibrosis associated with ischemic reperfusion injury, post-vasectomypain syndrome, fibrosis associated with rheumatoid arthritis,arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixedconnective tissue disease, fibrous proliferative lesions of the oralcavity, fibrosing intestinal strictures, Crohn's disease, glialscarring, leptomeningeal fibrosis, meningitis, systemic lupuserythematosus, fibrosis due to radiation exposure, fibrosis due tomammary cystic rupture, myelofibrosis, retroperitoneal fibrosis,progressive massive fibrosis, or symptoms or sequelae thereof, or otherdiseases or conditions resulting in the excessive deposition ofextracellular matrix components, such as collagen, which may be affectedby interventions within the TRβ pathway, or any combination thereof. 4.The method of any of claims 1-3 wherein said fibrosis, fibroticcondition or fibrotic symptom is a primary fibrosis.
 5. The method ofany of claims 1-4 wherein said fibrosis, fibrotic condition or fibroticsymptom is secondary to another condition.
 6. The method of any ofclaims 1-5 wherein said fibrosis, fibrotic condition or fibrotic symptomcomprises one or more of scleroderma, atherosclerosis, cardiac fibrosis,organ transplant fibrosis, muscle fibrosis, pancreatic fibrosis,bone-marrow fibrosis, liver fibrosis, fibrosis of the spleen, pulmonaryfibrosis, idiopathic pulmonary fibrosis, idiopathic interstitialfibrosis, diffuse interstitial fibrosis, interstitial lung disease,chronic interstitial lung disease, pneumoconiosis, silicosis,interstitial fibrosis, sarcoidosis, mediastinal fibrosis, cardiacfibrosis, atrial fibrosis, endomyocardial fibrosis, renal fibrosis,macular degeneration, keloid lesions, hypertrophic scar, nephrogenicsystemic fibrosis, injection fibrosis, fibrotic complications ofsurgery, fibrotic chronic allograft vasculopathy, fibrosis associatedwith ischemic reperfusion injury, arthrofibrosis, Dupuytren's disease,fibrous proliferative lesions of the oral cavity, fibrosing intestinalstrictures, glial scarring, leptomeningeal fibrosis, fibrosis due toradiation exposure, fibrosis due to mammary cystic rupture,myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis orany combination thereof.
 7. The method of any of claims 1-3 or 5 whereinsaid fibrosis, fibrotic condition or fibrotic symptom is secondary toone or more of glycogen storage disease type III (GSD III), glycogenstorage disease type VI (GSD VI), glycogen storage disease type IX (GSDIX), non-alcoholic steatohepatitis (NASH), cirrhosis, hepatitis,scleroderma, alcoholic fatty liver disease, atherosclerosis, asthma,cirrhosis of the gallbladder, diffuse parenchymal lung disease,interstitial pneumonitis, desquamative interstitial pneumonia,respiratory bronchiolitis, interstitial lung disease, chronicinterstitial lung disease, acute interstitial pneumonitis,hypersensitivity pneumonitis, nonspecific interstitial pneumonia,cryptogenic organizing pneumonia, lymphocytic interstitial pneumonia,emphysema, chronic kidney disease, Type H diabetes, maculardegeneration, chronic rejection in transplanted organs, post-vasectomypain syndrome, rheumatoid arthritis, dermatomyositis-polymyositis, mixedconnective tissue disease, Crohn's disease, meningitis, systemic lupuserythematosus, or symptoms or sequelae thereof, or other diseases orconditions resulting in the excessive deposition of extracellular matrixcomponents, such as collagen, which may be affected by interventionswithin the TRβ pathway, or any combination thereof.
 8. The method of anyof claims 1-7 wherein said fibrosis, fibrotic condition or fibroticsymptom is a symptom or sequela of GSD III, GSD VI, GSD IX, NonAlcoholic Steatohepatitis, cirrhosis of the liver or pancreas,Dupuytren's disease, scleroderma, idiopathic pulmonary fibrosis, oralcoholic fatty liver disease, or any combination thereof.
 9. A methodof treating a fibrosis, a fibrotic condition or a fibrotic symptom in asubject, comprising administering one or more compounds having astructure selected from the group consisting of:

or pharmaceutically acceptable salts thereof to a subject in needthereof.
 10. The method of claim 9 wherein said subject has one or moreconditions selected from glycogen storage disease type III (GSD III),glycogen storage disease type VI (GSD VI), glycogen storage disease typeIX (GSD IX), hepatitis, scleroderma, atherosclerosis, asthma, cardiacfibrosis, organ transplant fibrosis, muscle fibrosis, pancreaticfibrosis, bone-marrow fibrosis, liver fibrosis, cirrhosis of thegallbladder, fibrosis of the spleen, pulmonary fibrosis, idiopathicpulmonary fibrosis, diffuse parenchymal lung disease, idiopathicinterstitial fibrosis, diffuse interstitial fibrosis, interstitialpneumonitis, desquamative interstitial pneumonia, respiratorybronchiolitis, interstitial lung disease, chronic interstitial lungdisease, acute interstitial pneumonitis, hypersensitivity pneumonitis,nonspecific interstitial pneumonia, cryptogenic organizing pneumonia,lymphocytic interstitial pneumonia, pneumoconiosis, silicosis,emphysema, interstitial fibrosis, sarcoidosis, mediastinal fibrosis,cardiac fibrosis, atrial fibrosis, endomyocardial fibrosis, renalfibrosis, chronic kidney disease, Type II diabetes, maculardegeneration, keloid lesions, hypertrophic scar, nephrogenic systemicfibrosis, injection fibrosis, complications of surgery, fibrotic chronicallograft vasculopathy and/or chronic rejection in transplanted organs,fibrosis associated with ischemic reperfusion injury, post-vasectomypain syndrome, fibrosis associated with rheumatoid arthritis,arthrofibrosis, Dupuytren's disease, dermatomyositis-polymyositis, mixedconnective tissue disease, fibrous proliferative lesions of the oralcavity, fibrosing intestinal strictures, Crohn's disease, glialscarring, leptomeningeal fibrosis, meningitis, systemic lupuserythematosus, fibrosis due to radiation exposure, fibrosis due tomammary cystic rupture, myelofibrosis, retroperitoneal fibrosis,progressive massive fibrosis, or symptoms or sequelae thereof, or otherdiseases or conditions resulting in the excessive deposition ofextracellular matrix components, such as collagen, which may be affectedby interventions within the TRβ pathway, or any combination thereof. 11.The method of any of claims 9-10 wherein said condition is a primaryfibrosis.
 12. The method of any of claims 9-11 wherein said conditionhas fibrosis as a symptom.
 13. The method of any of claims 9-12 whereinsaid fibrosis, fibrotic condition or fibrotic symptom comprises one ormore of scleroderma, atherosclerosis, cardiac fibrosis, organ transplantfibrosis, muscle fibrosis, pancreatic fibrosis, bone-marrow fibrosis,liver fibrosis, fibrosis of the spleen, pulmonary fibrosis, idiopathicpulmonary fibrosis, idiopathic interstitial fibrosis, diffuseinterstitial fibrosis, interstitial lung disease, chronic interstitiallung disease, pneumoconiosis, silicosis, interstitial fibrosis,sarcoidosis, mediastinal fibrosis, cardiac fibrosis, atrial fibrosis,endomyocardial fibrosis, renal fibrosis, macular degeneration, keloidlesions, hypertrophic scar, nephrogenic systemic fibrosis, injectionfibrosis, fibrotic complications of surgery, fibrotic chronic allograftvasculopathy, fibrosis associated with ischemic reperfusion injury,arthrofibrosis, Dupuytren's disease, fibrous proliferative lesions ofthe oral cavity, fibrosing intestinal strictures, glial scarring,leptomeningeal fibrosis, fibrosis due to radiation exposure, fibrosisdue to mammary cystic rupture, myelofibrosis, retroperitoneal fibrosis,progressive massive fibrosis or any combination thereof.
 14. The methodof any of claims 9-13 wherein said fibrosis, fibrotic condition orfibrotic symptom comprises one or more of glycogen storage disease typeIII (GSD III), glycogen storage disease type VI (GSD VI), glycogenstorage disease type IX (GSD IX), hepatitis, scleroderma,atherosclerosis, asthma, cirrhosis of the gallbladder, diffuseparenchymal lung disease, interstitial pneumonitis, desquamativeinterstitial pneumonia, respiratory bronchiolitis, interstitial lungdisease, chronic interstitial lung disease, acute interstitialpneumonitis, hypersensitivity pneumonitis, nonspecific interstitialpneumonia, cryptogenic organizing pneumonia, lymphocytic interstitialpneumonia, emphysema, chronic kidney disease, Type II diabetes, maculardegeneration, chronic rejection in transplanted organs, post-vasectomypain syndrome, rheumatoid arthritis, dermatomyositis-polymyositis, mixedconnective tissue disease, Crohn's disease, meningitis, systemic lupuserythematosus, or symptoms or sequelae thereof, or other diseases orconditions resulting in the excessive deposition of extracellular matrixcomponents, such as collagen, which may be affected by interventionswithin the TRβ pathway, or any combination thereof.
 15. The method ofany of claims 9-14 wherein said fibrosis, fibrotic condition or fibroticsymptom is a symptom or sequela of GSD III, GSD VI, GSD IX, cirrhosis ofthe pancreas, Dupuytren's disease, scleroderma, idiopathic pulmonaryfibrosis, or alcoholic fatty liver disease, or any combination thereof.16. The method of any of claims 1-15, comprising administering acomposition comprising said compound and one or more pharmaceuticallyacceptable excipients.
 17. The method of any of claims 1-16 wherein saidcomposition is formulated for oral, intravenous, intraarterial,intestinal, rectal, vaginal, nasal, pulmonary, topical, intradermal,transdermal, transbuccal, translingual, sublingual, or opthalmicadministration, or any combination thereof.
 18. The method of any ofclaims 1-17 wherein said subject shows abnormal or excessive depositionof collagen.
 19. The method of any of claims 1-18 wherein said subjectshows abnormal or excessive deposition of collagen type
 1. 20. Themethod of any of claims 1-19 wherein said subject shows abnormal orexcessive deposition of collagen type 1a.
 21. The method of any ofclaims 1-20 wherein said subject shows abnormal or excessive depositionof collagen type III.
 22. The method of any of claims 1-21 wherein saidadministration of said compound results in the prevention, amelioration,or cure of said fibrosis, fibrotic condition, or fibrotic symptom. 23.The method of any of claims 1-22 wherein said administration of saidcompound results in the reduction in the amount of extracellular matrixproteins present in one or more tissues of said subject.
 24. The methodof any of claims 1-23 wherein said administration of said compoundresults in the reduction in the amount of collagen present in one ormore tissues of said subject.
 25. The method of any of claims 1-24wherein said administration of said compound results in the reduction inthe amount of Type I, Type Ia, or Type III collagen present in one ormore tissues of said subject.